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Therapy of superficial bladder cancer
Abstract
Intravesical therapy has been used in the management of superficial transitional cell carcinoma (TCC) of the urinary bladder (Ie, Ta, Tl, and carcinoma in situ [CIS]) with specific objectives that include treating existing/residual tumor, preventing recurrence of tumor, preventing disease progression, and prolonging survival. The initial clinical stage and grade remain the main determinant factors in survival irrespective of the treatment. Intravesical chemotherapy has shown a decrease in short-term tumor recurrence rates, but has had no positive impact on disease progression or prolongation of survival. Presently, bacillus Calmette-Guèrin vaccine (BCG) immunotherapy remains the most effective treatment and prophylaxis for TCC (Ta, Tl, CIS) and has positive outcome on tumor recurrence rate, disease progression, and prolongation of survival. Prostatic urethral mucosal involvement with bladder cancer can also be effectively treated with BCG intravesical immunotherapy. Interferons, keyhole limpet hemocyanin and photofrin-photodynamic therapy are under investigation in the management of TCC and early results are encouraging. This review highlights and summarizes the recent advances in intravesical therapy and prophylaxis of superficial TCC.
... The algorithm for the management of bladder cancer, unlike that for other malignancies, is focused primarily on the prevention of recurrence which is estimated as high as 40-60% at 12 months after initial treatment of papillary tumours (Hall et al, 1994). To reduce subsequent recurrence, measures such as intravesical chemotherapy with antineoplastic agents (Nseyo & Lamm 1994) and Bacillus Calmette-Guerin (BCG) (Herr et al, 1988) have been tried with some success. However, for effective prevention of recurrence, the only reliable option is to replaced the diseased urothelium, whether visible or not, with healthy transitional cell lining, a prospect which is technically difficult at this moment. ...
Photodynamic therapy (PDT) produces localised destruction of tissue with light after prior administration of a photosensitising agent. Connective tissue is relatively unaffected but attempts to treat the entire urothelium in the bladder using the photosensitiser Photofrin have led to detrusor muscle scarring and irritable, contracted bladders and obstructive uropathy. This thesis studied PDT on the normal rat bladder using the photosensitising agent, 5-aminolaevulinic acid (ALA). ALA solution was given intravesically, and the kinetics of the active derivative, protoporphyrin IX (PpIX) followed with fluorescence microscopy. Peak urothelial levels were seen at 5 hours, when treatment with 50J red light gave uniform urothelial necrosis without muscle damage which healed by regeneration. The PDT effect was enhanced by giving the iron chelator, CP94. Further studies looked at PDT on normal canine prostate using 3 photosensitisers: ALA, meso-tetra-(m-hydroxyphenyl)chlorin (mTHPC) and aluminium disulphonated phthalocyanine (A1S2Pc). Kinetic studies were undertaken on serial biopsies after sensitisation. Light was delivered interstitially and the animals killed up to 90 days later, revealing glandular necrosis (2.5cm diam. mTHPC, 1.2cm A1S2PC, 0.2cm ALA) but little effect on connective tissues, and no change in the gland size and shape. Urethral damage sometimes caused urinary retention which resolved in a week. Deliberate treatment of the sphincter in rats caused incontinence in 25%. Neoplastic areas of both prostate and bladder take up at least as much photosensitiser as adjacent normal tissue. Thus PDT using intravesical ALA is promising for carcinoma in situ of the bladder and preventing bladder tumour recurrence and PDT with mTHPC for prostate cancers localised to the gland, care being taken to avoid the sphincter. Both techniques are now ready for preliminary clinical trials.
... The majority of TCC (>70%) are diagnosed as superficial lesions and are easily cured by transurethral dissection and chemotherapy (2,3). However, these tumors have a high frequency of recurrence after transurethral dissection and some of them will progress to invasive and potentially fatal metastatic tumors (4). Cytoscopic examination and histological confirmation of bladder biopsy are currently the most reliable methods for therapeutic interventions and clinical outcome. ...
Background/aim:
The outcome of patients with advanced hepatocellular carcinoma (HCC) remains poor and therapeutic options, including sorafenib, the first anti-cancer drug proved to prolong survival in patients with advanced HCC, are limited. However, no clinically useful predictive biomarker for sorafenib has been reported.
Materials and methods:
We exploited two-dimensional gel electrophoresis coupled with mass spectrometry to find de-regulated proteins by using conditioning of a sorafenib-resistant HCC cell line, Huh7. Tumor samples from 60 patients with HCC treated with sorafenib were analyzed and correlated with survival outcome.
Results:
Comparative proteomics indicated three proteins including, 78 kDa glucose related protein (GRP78), 14-3-3ε, and heat shock protein 90β (HSP90β). The three proteins were over-expressed in sorafenib-resistant Huh7 cells. In HCC tumor samples from patients treated with sorafenib, 73% of tumor samples had a high expression of GRP78, 18% had high 14-3-3ε expression and 85% had high HSP90β expression. Among these, GRP78 was associated with the shortest progression-free survival of HCC patients treated with sorafenib.
Conclusion:
GRP78 can be a predictive biomarker in HCC patients treated with sorafenib. Strategies designed to inhibit the GRP78-related pathway may overcome sorafenib resistance.
... Х а р а к т е р и с т и к а б о л ь н ы х в з а в и с и м о с т и о т г р у п п ы Несмотря на то что 10-летняя выживаемость больных неинвазивным РМП достигает 95%, у части пациентов опухоль может прогрессировать в мышечно-инвазивную, в том числе с развитием метастазов [13,14]. Высокая частота рецидивов после ТУР мочевого пузыря обусловливает необходимость применения адъювантных методов лечения, наиболее эффективным из которых является иммунотерапия вакциной БЦЖ. ...
Background: Both bacillus Calmette-Gue’rin (BCG) and interferon-alpha (IFN-α) are active against urinary bladder cancer. In this studywe evaluate the therapeutic efficacy and toxicity of combined intravesical BCG plus IFN-α for treating non-invasive bladder cancer.Subjects and methods: A total of 149 patients (mean age 63.2 years) were enrolled for the study. The inclusion criteria were histologically verifiednon-invasive transitional cell carcinoma with intermediate and high risks of recurrence and progression. After transurethral tumor resection, all thepatients were randomized in three groups. Group 1 (n=60) was treated with a 6-week course of BCG, 125 mg, starting 14 to 21 days after TUR, Group2 (n=60) patients received 6-week instillations of BCG, 125 mg, plus IFN-α, 6 million units, Group 3 patients (n = 29) had 4-month courses ofintravesical IFN-α, 6 million units, twice daily during 3 consecutive days. A response was assessed by cystoscopy every 3 months after treatment.Results: A median follow-up of 30.9 months revealed recurrences in 26 (43.3%) patients in the BCG group, 8 (13.3%) patients in the BCG + IFN-αgroup and 18 (62.1%) patients in the IFN-α group. Progression to muscle invasion occurred in 12% and 7% in Groups 1 and 3, respectively, withno progression in Group 2 patients. Three-year relapse-free survival was higher in the BCG+IFN group (78.5% versus 62.6 and 40.2% in theBCG and IFN-α groups, respectively). There was no significant difference between the BCG groups in relapse-free survival. Monotherapy withIFN-α showed a significantly lower response rate than did BCG therapies (p = 0.007). Adverse reactions were observed in 25, 116, and 6.9% ofpatients from Groups 1, 2 and 3, respectively. Toxicity-related withdrawal and treatment delay were similar in both BCG groups. Comparison ofthe rate of adverse reactions revealed a significant difference between the BCG + IFN-α and BCG groups (p = 0.025). The respective rates ofmoderate-to-severe adverse reactions caused by treatment were 6.7 and 21.7% in the BCG+IFN-α and BCG groups, respectively (p = 0.013).Conclusions: Full-dose intravesical BCG plus IFN-α appears to be much effective than BCG and IFN-α monotherapies despite that there isno significant difference in this study. IFN-α monotherapy showed the lowest complication rate but a lower response rate than those withBCG therapies (p = 0.007). The co-administration of BCG and IFN-α displayed a significantly less complication rate and severe adversereactions (p = 0.025 and p = 0.013, respectively). Longer follow-up is required to validate these findings.
... Х а р а к т е р и с т и к а б о л ь н ы х в з а в и с и м о с т и о т г р у п п ы Несмотря на то что 10-летняя выживаемость больных неинвазивным РМП достигает 95%, у части пациентов опухоль может прогрессировать в мышечно-инвазивную, в том числе с развитием метастазов [13,14]. Высокая частота рецидивов после ТУР мочевого пузыря обусловливает необходимость применения адъювантных методов лечения, наиболее эффективным из которых является иммунотерапия вакциной БЦЖ. ...
The authors describe their first experience in using bipolar transurethral resection for a urinary bladder tumor. The obvious advantage of thistechnique over others suggests that in the immediate future the bipolar technology will serve as the gold standard instead of monopolar one.
... The majority of TCC (>70%) are diagnosed as superficial lesions and are easily cured by transurethral dissection and chemotherapy (2,3). However, these tumors have a high frequency of recurrence after transurethral dissection and some of them will progress to invasive and potentially fatal metastatic tumors (4). Cytoscopic examination and histological confirmation of bladder biopsy are currently the most reliable methods for therapeutic interventions and clinical outcome. ...
Background:
Bladder cancer is the most prevalent type of cancer of the urinary tract in Taiwan. In order to identify the molecular basis of bladder carcinogenesis, we analyzed the proteomic profiling of transitional cell carcinoma (TCC) cell lines to search for novel biomarkers for human bladder cancer.
Materials and methods:
Two human TCC cell lines (TSGH8301, Grade II and BFTC905, Grade III) were selected for proteomic analysis. The candidate genes were identified by tandem mass spectrometry.
Results:
Eight differentially-expressed spots were revealed by high resolution 2-D electrophoresis. Five genes were identified by spectrometry as showing higher expression in the TSGH8301 cells, i.e. heat-shock protein 27, maspin, prohibitin and glutathione S-transferase P1-1 and Chaperonin-containing t-complex polypeptide 1 β subunit. In contrast, S100A4 and annexin V exhibited higher levels in the BFTC905 cells. The differential expression patterns of the identified genes were confirmed by immunoblotting and further analyzed using a variety of TCC cell lines. Conculsion: Our studies implicate the potential role of these de-regulated proteins in bladder cancer and warrant further investigation in clinical samples.
... NMIBC is normally removed by surgery during a cystoscopy under general anesthesia, known as transurethral resection of bladder tumors (TURBT). Unfortunately, the high rate of recurrence and progression after TURBT means that adjuvant treatments may usually be required, such as intravesical chemotherapy using mitomycin C, epirubicin, or doxorubicin and/or immunotherapy using Bacillus Calmette-Guérin (BCG) vaccine [2][3][4][5]. However, recurrence rates still remain high, and progression is not eliminated after the combined therapies. ...
Photochemical internalization (PCI) is a novel technology for the release of a therapeutic molecule from endocytic vesicles into the cytosol of a cell. The release of molecules occurs after activation of an endocytic membrane-embedded photosensitizer by light. In this study uptake and localization of the photosensitizer disulfonated tetraphenyl chlorin (TPCS2a) were explored to optimize a PCI protocol in an orthotopic rat bladder tumor model.
Female Fischer F344 rats were intravesically instilled with 0.4×10(6) AY-27 transitional carcinoma cells before allowing tumor growth for 14 days. The photosensitizer TPCS2a was intravesically instilled at different concentrations, and bladders were excised after different time intervals. The retention, penetration, and localization of intratumoral TPCS2a were explored ex vivo using fluorescence spectroscopy and fluorescence microscopy to determine an optimal PCI protocol. These results were compared to histological analysis of necrotic areas after activation of intratumoral TPCS2a by red light (652 nm, 0.5 J/cm(2)).
A superficial distribution pattern of the photosensitizer TPCS2a was seen in bladder tumor tissue, and TPCS2a was almost cleared from the tumors after 72hours. The highest retention of TPCS2a was found at 24hours after instillation when using a concentration of 3 mg/ml.
An optimal PCI protocol was defined for the tumor model, including a 24-hour TPCS2a-to-light interval and a dose of 3 mg/ml TPCS2a. This protocol will be utilized for the study of PCI-enhanced therapeutic effects on non-muscle invasive bladder cancer, using a potent chemotherapeutic under an optimal light dose.
Copyright © 2014 Elsevier B.V. All rights reserved.
... The best results are obtained from intravesical Bacillus Calmette Guerin (BCG) instillations into the bladder following TURBT. 1,2) However, as a significant proportion of patients with bladder cancer do not respond to BCG therapy and side effects are known to occur, 3) alternative modalities of treatment are being evaluated. ...
Lactic acid bacteria are known to have beneficial effects on the host, such as preventing carcinogenesis. The present study was designed to evaluate the chemopreventive effects of Lactobacttlus rhamnosus strain GG (LGG) in suppressing bladder cancer formation in a murine subcutaneous model of bladder cancer involving the inoculation of MB49 cells in C57B/L6 mice. After tumor implantation, one group of mice (n=8) was fed LGG immediately. The remaining mice that had tumors between 0.03–0.1 cm3 were divided into two groups: those fed LGG after 7 days (n=7) and those fed saline (n=7). A second group of mice without any inoculation of MB49 cells was fed either LGG (n=10) or saline (n=10) and served as non-tumor-bearing controls. LGG was administered orally at 1.6×l08 colony-forming units daily. Mice fed LGG immediately after tumor cell implantation formed smaller tumors and some did not develop tumors (2 out of 8 mice), when the tumor burden was small. The level of spleen CD3, CD4 and CD8a T lymphocytes, as well as natural killer cells in mice fed immediately with LGG was also higher than that in control tumor-bearing mice. There was an increase in lymphocytes and granulocytes in tumor sections, especially from the immediately fed group as compared to the controls. Our results suggest that oral consumption of LGG may prevent tumor growth via modulation of the immune system. The potential of LGG as an adjunct therapy in the treatment of bladder cancer could be further explored.
... Prior to checking the statistical heterogeneity among the studies, it should be pointed out that, from 1980 to the present, there have been no great technical advances or changes in the methods for treating patients with superficial bladder carcinoma, such as the method for TUR-Bt, intravesical instillation of chemotherapeutics with the objective of preventing tumor recurrence, or methods for the detection of tumor recurrence (cystoscopic examination). 18,19 The five JU-CRGA studies employed different patient selection criteria, and, for that reason, the patient background factors show some differences among the studies (in particular, the second study was conducted only in patients with primary tumors). Accordingly, the patients included in the studies were classified into four subgroups on the basis of their background factors, and it was confirmed that there was no heterogeneity among the studies in relation to both the prophylactic effect of the intravesical chemotherapy on tumor re- currence and the recurrence rate in the untreated control patients within each of the subgroups. ...
BACKGROUND
The effect of intravesical instillation of doxorubicin or epirubicin after transurethral resection (TUR) was estimated from the data of five randomized clinical trials in Japan. The authors provided the estimated hazard function plots with a smoothing technique, to evaluate the prophylactic effect of an intravesical therapy over time and to estimate the natural history of superficial bladder carcinoma.METHODS
Data on a total of 1732 patients from 5 studies of the Japanese Urological Cancer Research Group who were eligible to receive doxorubicin and epirubicin were analyzed. The patients were divided into four subgroups based on their background characteristics. Their tumors were categorized as “primary and solitary,” “primary and multiple,” “recurrent and solitary,” or “recurrent and multiple.”RESULTSMultivariate analysis revealed that intravesical instillation reduced the risk of recurrence to about one-half to two-thirds compared with the controls. The shapes of the graphs that estimated the hazard function for patients with no prophylaxis indicated that multiple tumors showed an earlier peak of recurrence than solitary tumors and recurrent tumors had a higher hazard of recurrence than primary tumors. Graphic presentation of the hazard function in each subgroup suggested that the effect of prophylaxis continued for 500 days after TUR but not for longer.CONCLUSIONS
This analysis indicated that there are two patterns of tumor recurrence of superficial bladder carcinoma after TUR, namely, early phase and late phase. Intravesical chemotherapy may be effective mainly in reducing the hazard for recurrence in the early phase. Cancer 1999;86:1818–26. © 1999 American Cancer Society.
... Tumor necrosis is a combined result of direct cell killing (Penning et al., 1994), occlusion of tumor blood vessels (Henderson et al., 1985), and an acute inflammatory reaction (Krosl et al., 1995). PDT has been used to treat many types of cancer, including colon, bladder, lung, esophageal, and head-andneck cancers (Fromm et al., 1996;Nseyo and Lamm, 1996;Furuse et al., 1993;Savary et al., 1997). ...
Coupling of photosensitizers to tumor-selective monoclonal antibodies (MAbs) is an attractive option for improving the selectivity of photodynamic therapy (PDT). For this purpose, hydrophilic sensitizers would be most suitable because of their solubility in water. However, such sensitizers are known to be ineffective in PDT, probably because they cannot readily pass the cell membrane and reach the critical intracellular target. We used the model compound TrisMPyP-ΦCO2H, a hydrophilic porphyrin derivative, to test the hypothesis that hydrophilic photosensitizers might become of therapeutic value when directed into the tumor cell by use of internalizing MAbs. TrisMPyP-ΦCO2H was conjugated using a labile ester. Conjugates showed no impairment of integrity on SDS-PAGE, full stability in serum in vitro, and optimal immunoreactivity when the sensitizer:MAb ratio was ≤3. At higher molar ratios, the solubility of the conjugates decreased. In vitro internalization experiments showed that TrisMPyP-ΦCONH–125I-cMAb U36 and TrisMPyPΦCONH–125I-mMAb 425 conjugates were internalized by A431 cells, in contrast to TrisMPyP-ΦCONH–125I-mMAb E48 conjugates. Data on the in vitro efficacy of PDT with MAb-conjugated TrisMPyP-ΦCO2H showed that the internalizing cMAb U36 and mMAb 425 conjugates were phototoxic to A431 cells, while the non-internalizing E48 conjugate and the unconjugated sensitizer were not. Biodistribution data of conjugates with sensitizer:125I-cMAb U36 ratios varying from 1:1 to 3:1 in tumor-bearing nude mice revealed selective accumulation in the tumor. Conjugates with higher molar ratios were cleared more rapidly from the blood than the unconjugated 125I-cMAb U36, resulting in lower tumor uptake but similar tumor-to-blood ratios. Our data suggest that hydrophilic photosensitizers might have therapeutic value when targeted to tumors by internalizing MAbs. Int. J. Cancer 88:108–114, 2000. © 2000 Wiley-Liss, Inc.
... Approximately 60% of superficial TCCs recur, but most never progress to muscle invasive cancer and thus their associated mortality is low. However, 20–25% of superficial TCCs progress over time to myoinvasive TCCs that pose a significant risk of morbidity and mortality for patients (Nseyo and Lamm 1996). To illustrate the associated clinical dilemma, one study shows that 13 of 62 patients (21%) diagnosed initially with superficial Ta or T1 well-differentiated grade I TCC eventually died of muscle invasive bladder cancer (Bane et al. 1996). ...
Elevation of p16, the CDKN2/p16 tumor suppressor gene (TSG) product, occurs at senescence in normal human uroepithelial cells (HUC). Immortal HUCs and bladder cancer cell lines show either alteration of p16 or pRb, the product of the retinoblastoma (RB) TSG. In addition, many human cancers show p16 or pRb alteration along with other genetic alterations that we associated with immortalization, including +20q and -3p. These observations led us to hypothesize that p16 elevation plays a critical role in senescence cell cycle arrest and that overcoming this block is an important step in tumorigenesis in vivo, as well as immortalization in vitro. Using a novel approach, we tested these hypotheses in the present study by examining p16 and pRb status in primary culture (P0) and after passage in vitro of transitional cell carcinoma (TCC) biopsies that represented both superficial bladder tumors and invasive bladder cancers. We demonstrated that all superficial TCCs showed elevated p16 after limited passage in vitro and then senesced, like normal HUCs. In contrast, all muscle invasive TCCs contained either a p16 or a pRb alteration at P0 and all spontaneously bypassed senescence (P = 0.001). Comparative genomic hybridization (CGH) was used to identify regions of chromosome loss or gain in all TCC samples. The application of a statistical model to the CGH data showed a high probability of elevated alteration rates of +20q11-q12 (0.99) and +8p22-pter (0.94) in the immortal muscle invasive TCCs, and of -9q (0.99) in the superficial TCCs. Three myoinvasive TCCs lost 3p13-p14. In this study, four of six myoinvasive TCCs also showed TP53 mutation that associated well with genome instability (P = 0.001), as previously hypothesized. Notably, TP53 mutation, which has been used as a marker of tumor progression in many human cancers, was less significant in associating with progression in this study (P = 0.04) than was p16 or pRb alteration (P = 0.001). Thus, these data support a new model in which overcoming senescence plays a critical role in human cancer pathogenesis and requires at least two genetic changes that occur in several combinations that can include either p16 or pRb loss and at least one additional alteration, such as +20q11-q12, -3p13-p14, or -8p21-pter.
... These combined effects result in tumor necrosis. PDT has been applied for noninvasive treatment of many types of cancer, including colon, bladder, lung, and head and neck cancer (5)(6)(7)(8). ...
A limitation of photodynamic therapy is the lack of tumor selectivity of the photosensitizer. To overcome this problem, a protocol was developed for coupling of meta-tetrahydroxyphenylchlorin (mTHPC), one of the most promising photosensitizers, to tumor-selective monoclonal antibodies (MAbs). mTHPC was radiolabeled with 131I to facilitate the assessment of the in vitro and in vivo behavior. After the modification to 131I-mTHPC-(CH2COOH)4, thus increasing the water solubility and creating a functional moiety suitable for coupling, conjugation was performed using a labile ester. Insoluble aggregates were not formed when mTHPC-MAb conjugates with a molar ratio of up to 4 were prepared. These conjugates showed a minimal impairment of the integrity on SDS-PAGE, full stability in serum in vitro, and an optimal immunoreactivity. To test the in vivo behavior of the mTHPC-MAb conjugates, the head and neck squamous cell carcinoma-selective chimeric MAb U36 was used in head and neck squamous cell carcinoma-bearing nude mice. Biodistribution data showed that the tumor selectivity of cMAb U36-conjugated mTHPC was increased in comparison with free mTHPC, despite the fact that conjugates with a higher mTHPC:MAb ratio were more rapidly cleared from the blood. Preliminary results on the in vitro efficacy of photodynamic therapy with MAb-conjugated mTHPC showed that mTHPC coupled to the internalizing murine MAb 425 exhibited more phototoxicity than when coupled to the noninternalizing chimeric MAb U36.
... Despite advances in endoscopic and intravesical chemotherapeutic procedures, superficial bladder cancer still has a high recurrence and progression rate. 1 Currently, the most successful treatment involves weekly instillation of 'live' BCG 2,3 into the bladder for 2 h. Although effective, side-effects such as dysuria, haematuria, frequency and cystitis are common and sometimes severe. ...
the murine urothelial cell line, mb49 was transfected with the reporter gene pcmvlacz using a number of commercial transfection agents. the transfection efficiency of these agents, as determined by beta-galactosidase activity, is in the order of dotap>superfect>Fugene. The addition of methyl-beta-cyclodextrin solubilized cholesterol (MBC) to Dotap and Superfect further improved their transfection efficiency by 3.8-fold and 2.6-fold, respectively. beta-Galactosidase activity was detectable within 1 h of transfection and peaked at 48 h. Nuclear and cytoplasmic separation showed that with Dotap + methyl-beta-cyclodextrin solubilized cholesterol (DMBC), the DNA plasmid complex was found in both the nucleus and the cytoplasm. In vivo, murine bladders were transfected with an intravesical instillation of DMBC + DNA for 2 h. Two days later the bladder, lungs, liver, spleen and heart were assayed for the presence of the beta-galactosidase gene by staining and PCR. Expression of the gene was confined to the bladder. Both in vitro and in vivo expression was observed after as little as a 15 min exposure to DMBC:DNA. Expression of the marker gene was present up to 30 days after transfection in vivo. From our data it appears that DMBC is the best nonviral agent for the transfection of urothelial cells in vitro and in vivo.
... The best results are obtained from intravesical Bacillus Calmette Guerin (BCG) instillations into the bladder following TURBT. 1,2) However, as a significant proportion of patients with bladder cancer do not respond to BCG therapy and side effects are known to occur, 3) alternative modalities of treatment are being evaluated. ...
Lactic acid bacteria are known to have beneficial effects on the host, such as preventing carcinogenesis. The present study was designed to evaluate the chemopreventive effects of Lactobacillus rhamnosus strain GG (LGG) in suppressing bladder cancer formation in a murine subcutaneous model of bladder cancer involving the inoculation of MB49 cells in C57B / L6 mice. After tumor implantation, one group of mice (n = 8) was fed LGG immediately. The remaining mice that had tumors between 0.03 - 0.1 cm(3) were divided into two groups: those fed LGG after 7 days (n = 7) and those fed saline (n = 7). A second group of mice without any inoculation of MB49 cells was fed either LGG (n = 10) or saline (n = 10) and served as non-tumor-bearing controls. LGG was administered orally at 1.6 x 10(8) colony-forming units daily. Mice fed LGG immediately after tumor cell implantation formed smaller tumors and some did not develop tumors (2 out of 8 mice), when the tumor burden was small. The level of spleen CD3, CD4 and CD8a T lymphocytes, as well as natural killer cells in mice fed immediately with LGG was also higher than that in control tumor-bearing mice. There was an increase in lymphocytes and granulocytes in tumor sections, especially from the immediately fed group as compared to the controls. Our results suggest that oral consumption of LGG may prevent tumor growth via modulation of the immune system. The potential of LGG as an adjunct therapy in the treatment of bladder cancer could be further explored.
... The overall 10-year survival rate of patients with superficial disease is approximately 80%, ranging from 50% to more than 95%, depending on the grade of the tumor [3,4]. A recurrence as high as 40-80% in patients affected by TCC has been reported and approximately 20% of tumors initially diagnosed as superficial will progress to invade the muscle or become metastatic [5,6]. Complete transurethral resection (TURBT) of superficial disease followed by intravesical immunotherapy in patients at risk for recurrence or progression seems to improve the outcome [7]. ...
Intravesical instillation of Bacillus Calmette-Guerin (BCG) is used with efficacy and safety in the treatment of patients with intermediate and high-risk superficial bladder carcinoma. Arthralgia and/or arthritis is one of the rare severe complications following intravesical BCG immunotherapy. We searched MEDLINE in order to analyze the frequency of this clinical complication, its pathogenesis and outcome. The electronic search was conducted using the following key words: "BCG immunotherapy" and "Arthritis, arthralgias and BCG immunotherapy". At the end of a process of abstract analysis, 48 papers were included in the systematic review. All the selected papers, except one that was a clinical review, described at least one case of arthritis after BCG therapy. The BCG immunotherapy resulted to be safe and efficacious in the treatment of bladder cancer; the development of reactive arthritis is rare and can evolve in a chronic process. The review of the literature highlighted that reactive arthritis following BCG intravesical instillation is a complication usually well controlled with the discontinuation of the immunotherapy and nonsteroidal anti-inflammatory drugs (NSAIDs) treatment. Only a small portion of patients with a particular genetic background will develop a chronic process.
... The majority of the bladder tumors (.70%) are diagnosed as superficial and easily treated by transurethral dissection and chemotherapy [2,3]. But these tumors exhibit a high frequency of recurrence and some of them will progress to muscle-invasive and metastatic tumors and thus pose a serious threat to patient survival [4]. The pathological staging and grading system is currently the most significant factor for therapeutic interventions and clinical outcome. ...
To better understand the carcinogenesis of bladder cancer in Taiwan, we utilized the proteomic approach to search for potential biomarkers of transitional cell carcinoma (TCC). Analysis by 2-DE and MS/MS indicated that seven proteins are down-regulated and three proteins up-regulated in grade III samples as compared with those of grade II. Of these deregulated proteins, fatty acid binding proteins, annexin V, heat-shock protein 27, and lactate dehydrogenase have been shown to be associated with bladder cancer. Our studies also found altered expression of a group of proteins that have not been documented previously in bladder cancer, including annexin I, 15-hydroxyprostaglandin dehydrogenase, galectin-1, lysophospholipase and mitochondrial short-chain enoyl-coenzyme A hydratase 1 precursor. These results illustrate a pattern of differential protein expression between low- and high-grade tumors and it may be utilized as the molecular fingerprinting of a subset of bladder cancers. In addition, the present study provides a valuable resource in the study of pathological mechanisms in cancers of urothelial origin. The immunohistochemical staining of grade II and III TCC samples with antiserum to annexin I protein was utilized to confirm that the annexin I protein is up-regulated in grade III TCC.
... More than 90% of patients throughout the world diagnosed with bladder cancer have transitional cell carcinoma (TCC). 2 Patients with superficial tumors (carcinoma in situ [CIS], Ta, T1) account for 70-85% of all newly diagnosed cases throughout the world. [3][4] The first choice of treatment for stages Ta and T1 disease is transurethral resection (TUR). A major problem in the treatment of superficial TCC of the bladder is the high incidence of tumor recurrence following TUR. ...
For the evaluation of anti-human bladder cancer immunotoxin approaches, the orthotopic nude murine model that mimics the human counterpart is essential for preclinical evaluation of new treatment modalities. The objective of this study was to develop and characterize such a model. To accomplish this, the established human bladder transitional cell carcinoma (TCC) cell line, BIU-87, was transplanted orthotopically into immunodeficient nude mice. BIU-87 TCC cells were grown in monolayer cell culture and instilled intravesically as single cell suspensions into bladders that had been conditioned with mild acid washing. Tumor growth was assessed weekly by subjecting the mice to magnetic resonance imaging (MRI). At intervals following implantation and MRI tumor detection, the animals were sacrificed for necropsy, histological examination and immunocytochemical studies. The overall tumor establishment was 93% (52/56 mice) at 7-36 days, while in a subgroup of animals sacrificed at 12-13 days, 40 out of 42 animals (95%) developed TCC, the majority of which was superficial. Tumor stage was assessed by gross pathology and light microscopy. Histological examination of the tumor specimens confirmed the presence of grade II-III TCC. Immunocytochemistry confirmed that the tumor model maintained the features of BIU-87 cells. The changes seen on MRI correlated well with the extent of tumor invasion identified histologically. Carcinoma in situ could be detected histologically 7-9 days post-inoculation, and progressed to papillary tumor or invasive disease thereafter. The orthotopic BIU-87 TCC model is highly reproducible and is ideal for preclinical studies on experimental intravesical therapies.
The prophylactic effect of an oral Lactobacillus casei preparation (Biolactis powder: BLP) on the recurrence of superficial bladder cancer and the mechanisms involved are reviewed. The immunopotentiating effect of BLP was assessed in tumor-bearing BALB/c mice and its inhibitory effect on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced bladder carcinogenesis was assessed in male Wistar rats and C3H/He mice. The safety and efficacy of BLP in preventing bladder cancer recurrence after transurethral resection were assessed in two clinical trials. In BALB/c mice, BLP reduced the growth of secondary tumors and augmented proliferation and cytokine production by splenocytes. It also significantly inhibited bladder tumor formation in rats and mice, and the tumors developing in BLP-treated animals showed a lower grade of malignancy. In a randomized clinical trial, BLP significantly prolonged the recurrence-free interval by 1.8-fold compared to that in the controls. In a double-blind trial, BLP significantly delayed recurrence in patients with multiple primary or single recurrent tumors and downgraded the recurrent lesions. BLP appears to modify the intestinal flora and reduce the production of chemical carcinogens, resulting in significant antitumor and prophylactic activity in animals and humans.
It has been a provocative experience to share my thoughts on tumor heterogeneity. This is not a subject I previously pondered in specific terms, but when I began to review the subject, it was apparent that the problem of tumor heterogeneity is one of the fundamental problems of cancer therapy [1–12]. Treating cancer is analogous to shooting at a continuously moving target. As our comprehension of cancer improves through scientific advances, the more scientific strategic approaches to control this devastating disease appear to be akin to Don Quixote throwing our national resources at the windmills in the fields outside Barcelona [13]. This is not to suggest that the expenditures have not resulted in remarkable scientific achievements but rather a successful conclusion has not been reached.
Purpose: Orthotopic tumor models are comparable to the human situation with regard to metastatic pattern. The purpose of this study was to optimize the orthotopic murine bladder cancer model with regard to tumor take rate and to develop a model to investigate the effects of intravesical therapeutic agents on tumor progression and survival. We used this optimized model to clarify the influence of anti-inflammatory drugs on the efficacy of intravesical BCG in bladder cancer treatment. Materials and Methods: Syngeneic bladder cancer cells (MB49) of differing concentration were instilled orthotopically. The intravesical catheter was pinched off after instillation and was left in place for the duration of anesthesia. Using this method we ensured a dwelling time of 3 h and a tumor take rate of 100%. To verify whether this modification maintained its sensitivity to topical immunotherapy, an initial tumor load of 100000 MB 49 cells was given, and mice were treated intravesically with BCG or phosphate-buffered saline. In the next step 75 mice were randomized into 5 groups of 15 animals. Intravesical treatment was done with phosphate buffered saline (PBS, group 1), BCG (Group), BCG and acetylic salicylic acid (ASA, Group 3), BCG and pentoxifylline (POF, group 4) and autoclaved BCG (aBCG, group 5). Results: The modification of instillation resulted in tumor take rate of 100%, independent of the number of instilled cells. Even with the highest tumor load, BCG therapy improved survival and reduced bladder weight significantly, as compared to PBS. PBS and aBCG had no effect on tumor growth, whereas animals treated with viable BCG alone and in combination with POF or ASA, showed a significant reduction in bladder weight. Mice treated with BCG, BCG + ASA, BCG + POF showed a significantly higher proportion of survival rate compared to PBS alone. Autoclaved BCG had no therapeutic efficacy. Conclusion: Modification of the orthotopic bladder tumor model (MB 49) results in a tumor take rate of 100% and maintains its susceptibility to topical immunotherapy. The efficacy of BCG therapy in murine orthotopic bladder cancer is dependent on BCG viability and is not compromised by ASA or POF. Clinical trials to evaluate the efficacy of routine ASA or POF to reduce BCG side effects in patients should be initiated.
Eighty percent of bladder tumors are confined to mucosa (CIS, Ta) or submucosa (T1) at initial presentation. The main problems in superficial bladder cancer are recurrence and progression in spite of resection. To prevent these, several intravesical agents are used. The most effective of these agents is bacillus Calmette-Guerin (BCG). But the questions about its mechanism, optimal dose and clinical use remain unclear.
The anthracycline epirubicin has been investigated for intravesical use in patients with superficial bladder cancer. In multicentre, randomised trials, prophylaxis with intravesical epirubicin 30 to 80mg after transurethral resection (TUR) was more effective than no prophylaxis in the prevention of disease recurrence. Intravesical prophylaxis with epirubicin was as effective as that with equivalent dosages of doxorubicin after TUR. Data are conflicting concerning the relative efficacy of intravesical epirubicin and bacillus Calmette-Guerin (BCG) in patients at intermediate risk of recurrence after TUR, but epirubicin was less effective than BCG in those at high risk. The efficacy and tolerability of prophylaxis with epirubicin relative to that with mitomycin is not yet established. The efficacy of epirubicin as prophylaxis after TUR in combination with BCG or interferon-α-2b, or as treatment in patients with superficial bladder cancer has been evaluated in small, noncomparative trials, but requires clarification.
Adverse events associated with intravesical epirubicin were generally mild and transient. The most common adverse events were localised to the bladder (cystitis, haematuria and urinary tract infection). Systemic adverse events (cardiac, haematological or related to hypersensitivity) were not reported in mn, and when reported generally occurred ited generally occurred in ≤5% of patients who received the drug. Intravesical epirubicin was generally tolerated as well as intravesical doxorubicin and was associated with a lower incidence of mild chemical cystitis in 1 clinical trial. The incidence of adverse events associated with intravesical epirubicin was markedly lower than that associated with intravesical BCG.
Conclusions: Intravesical epirubicin has shown efficacy in preventing disease recurrence after TUR of superficial bladder cancer. In comparison with equivalent dosages of doxorubicin, the efficacy of epirubicin for this indication is generally similar, and the tolerability profile may be more favourable. Epirubicin is less effective than BCG as intravesical prophylaxis in patients at high risk of recurrence after TUR; the relative efficacy of epirubicin and BCG after TUR in patients at intermediate risk is not yet clear. Intravesical epirubicin is generally tolerated better than BCG. Intravesical epirubicin may be used as prophylaxis after TUR in patients who are at low or intermediate risk of recurrence of superficial bladder cancer.
Pharmacodynamic Properties
Epirubicin, an epimer of the anthracycline doxorubicin, is an antineoplastic agent that inhibits DNA replication, transcription and repair by binding to the nucleic acid. Epirubicin was at least as cytotoxic as doxorubicin in vitro in bladder tumour cell lines. It was less cytotoxic to normal than to neoplastic transitional epithelial cells. Importantly, epirubicin is less cytotoxic than doxorubicin to haematopoietic progenitor cells in vitro and to cardiac tissue in vivo.
Resistance to epirubicin was reversed in bladder tumour cell lines in vitro by verapamil, valspodar, increasing pH, estramustine, lonidamine or meglumine-γ-linoleic acid. In patients with superficial bladder cancer, combination therapy with epirubicin and verapamil achieved higher concentrations of the drug than epirubicin alone in neoplastic and normal transitional epithelium prior to TUR, and this was correlated with clinical response.
Pharmacokinetic Properties
Before it can be absorbed systemically, intravesically administered epirubicin must enter the transitional epithelial cells which line the bladder. 58 to 84% of each dose was recovered from the bladder in washes and voided urine after each intravesical instillation of epirubicin 30 to 80mg. Tumours absorbed 2- to 10-fold more epirubicin than normal transitional epithelium in patients with superficial bladder cancer who received the drug intravesically. Systemic absorption of intravesically administered epirubicin is minimal. Peak plasma concentrations were 3 to 9 μg/L in most patients who received intravesical epirubicin 20 to 50mg.
Epirubicin metabolism is similar to that of doxorubicin except that, unlike its stereoisomer, epirubicin undergoes β-glucuronidation. After intravenous administration, the terminal elimination half-life of epirubicin (15 to 45 hours) is 40 to 70% shorter than that of doxorubicin, probably because of the difference in β-glucuronidation. Clearance of intravenously administered epirubicin was 40 to 87 L/h. The primary route of excretion was the bile, and patients with hepatic dysfunction exhibited elevated plasma drug concentrations and reduced clearance compared with those with normal hepatic function when they received epirubicin intravenously.
Clinical Efficacy in Superficial Bladder Cancer
Prophylaxis. Intravesical epirubicin was effective in the prevention of tumour recurrence after TUR in multicentre, randomised clinical trials in patients with superficial bladder cancer. The optimal dosage regimen has not yet been established. However, single dose epirubicin was as effective as an induction and maintenance protocol in patients at low risk of recurrence, but was less effective in patients at intermediate or high risk of recurrence. Overall recurrence rates were lower with epirubicin 40 to 80mg (single dose or induction and maintenance; 0.072 to 0.186 per year) than with no prophylaxis (0.241 to 0.378 per year). Similarly, mean recurrence-free intervals were longer with epirubicin than with no prophylaxis.
The overall efficacy of intravesical prophylaxis with epirubicin after TUR was similar to that with identical dosages of doxorubicin (induction and maintenance). Overall recurrence rates were 0.100 or 0.110 per year with epirubicin 50mg, 0.072 per year with epirubicin 80mg and 0.180 or 0.142 per year with doxorubicin 50mg in 2 trials; the difference was statistically significant when epirubicin (both doses combined) was compared with doxorubicin in 1 of these trials. However, in 2 other studies, simple recurrence rates were similar with epirubicin 30mg (25% in both studies) or doxorubicin 30mg (27 or 28%). Mean recurrence-free intervals were similar in patients who received epirubicin 30 to 80mg or doxorubicin 30 or 50mg.
The overall clinical efficacy of induction and maintenance prophylaxis with epirubicin versus that with bacillus Calmette-Guerin (BCG) varied in clinical trials. Overall recurrence rates did not differ significantly with epirubicin 50mg (0.186 to 0.252 per year) or BCG 150mg or 5 × 108 colony forming units [cfu] (0.134 to 0.167 per year); similarly, recurrence rates did not differ significantly between these 2 agents in patients with Ta, G1, G2, single, multiple, primary or recurrent tumours. However, recurrence rates were consistently significantly higher with epirubicin than with BCG in patients with T1 and/or G3 tumours. The trends in recurrence-free intervals were similar to those in recurrence rates in trials of prophylactic epirubicin versus BCG. In 1 large trial in patients at intermediate or high risk of recurrence after TUR, overall recurrence-free rates 2 years after TUR were significantly lower with epirubicin than with BCG; this trial was reported as an abstract. In contrast, recurrence-free rates were similar with the 2 agents 2, 3 or 5 years after TUR in smaller trials in patients at low, intermediate or high risk of recurrence. Data are insufficient to establish the efficacy of epirubicin in comparison with interferon-α-2b or mitomycin.
Similar to other intravesical agents, epirubicin did not appear to reduce the rate of progression of tumours which recurred after TUR. The rate of progression of tumours to stage T2 (muscle-invasive disease) was generally similar with epirubicin and doxorubicin or BCG.
Prophylaxis with epirubicin in combination with BCG was evaluated in a few clinical trials. In 1 comparative trial, recurrence-free interval tended to be longer with epirubicin and BCG than with BCG alone after TUR; recurrence and progression rates appeared to be lower with the combination of epirubicin and BCG but did not differ significantly between the 2 regimens. In addition, combination prophylaxis with epirubicin and interferon-α-2b after TUR tended to be more effective than epirubicin alone, interferon-α-2b or no prophylaxis in trials in patients with superficial bladder cancer.
Treatment. Intravesical epirubicin 30 to 60mg as treatment achieved variable complete response rates (range 6 to 67%) in noncomparative trials. In a small number of patients with carcinoma in situ, treatment with epirubicin 30 to 80mg achieved dose-related complete response rates of 43 to 70%.
Tolerability
The overall incidence of adverse events in trials of intravesical epirubicin 50mg ranged from 16 to 25%. The frequency of adverse events tended to increase with epirubicin dose but not number of instillations. Most adverse events associated with intravesical epirubicin were mild and transient; the most common were localised to the bladder and included chemical cystitis (10 to 38% of patients), urinary tract infection (2 to 13%) and haematuria (2 to 33%). Contracted bladder or haemorrhagic cystitis occurred in 1 to 6% of patients in a few trials.
Systemic adverse events were not reported in many trials, and usually occurred in ≤5% of patients who received intravesical epirubicin. Cardiac adverse events (myocardial infarction, cerebrovascular accident, angina pectoris or atrioventricular block) were reported in only 2 studies, and occurred in 2 to 9% of patients. Thrombocytopenia and haemoglobinaemia each occurred in 3% of patients in 2 different trials, but otherwise there were no reports of myelosuppression. Hypersensitivity was reported in 0 to 8% of patients in different trials; 1 patient died of a severe allergic reaction after receiving intravesical epirubicin. Nonspecific systemic symptoms (flu-like symptoms, malaise, fever, nausea, vomiting, anorexia or rash) were reported in 0 to <5% of patients who received intravesical epirubicin.
Overall, the type and incidence of local adverse events was similar with epirubicin and doxorubicin. The incidence of mild chemical cystitis tended to be lower with epirubicin 50 or 80mg (8 to 19%) than with doxorubicin 50mg (21 or 25%); the difference was significant in 1 trial. Systemic adverse events occurred in no epirubicin recipients and 5% of doxorubicin recipients in 1 study, but were not reported in other comparative trials.
The incidence of local adverse events was usually lower with epirubicin than with BCG in comparative trials. Cystitis occurred in 25 to 38% of recipients of epirubicin 50mg and 67 to 79% of recipients of BCG 150mg or 5 × 108 cfu in 3 trials; the incidence of this adverse event was similar with epirubicin 80mg and BCG 75mg (62 or 61%) in a fourth trial. Haematuria occurred less often in patients who received epirubicin 50mg (13 to 16% of patients) than in those who received BCG 150mg or 5 × 108 cfu (23 or 24% of patients), but more often with epirubicin 80mg than BCG 75mg (26 vs 10% of patients). Adverse events caused temporary delays in treatment more often with epirubicin than with BCG. Nonspecific systemic adverse events occurred markedly less often with epirubicin (0 to 18%) than with BCG (13 to 31%) in comparative trials.
The incidence of cystitis was similar with epirubicin or mitomycin (11%) in a single trial, but the comparative tolerability of these 2 agents has not been fully investigated. In trials of combination prophylaxis with epirubicin and BCG, the incidence of adverse events may have been related to the treatment regimen, and was lower with epirubicin in combination with BCG than with BCG alone in 1 comparative trial. Adverse events were similar in patients who received epirubicin alone or epirubicin in combination with interferon-α-2b as prophylaxis in clinical trials.
Dosage and Administration
Intravesical epirubicin is indicated for prophylaxis after TUR or for treatment in patients with superficial bladder cancer. There is no recommended dosage, but the most common dosage for prophylaxis is induction with epirubicin 50mg in 50ml saline once a week for 4 weeks, then maintenance with the same dose once a month for 11 months, according to the manufacturer. For treatment, the dosage suggested by the manufacturer is epirubicin 50mg once a week for 8 weeks; the dose can be increased to 80mg in patients with carcinoma in situ, depending on individual tolerability.
Each dose of epirubicin should be instilled in the bladder through a small catheter and retained for 1 hour. Patients should avoid fluids for 12 hours before each instillation and not void until the end of the instillation. Patients who have already received the maximum cumulative dose of other anthracyclines, who have a history of hypersensitivity to anthracyclines or who developed marked myelo-suppression during previous anthracycline exposure should not receive intravesical epirubicin.
Transitional cell carcinoma (TCC) of the bladder has a 40-70% local recurrence rate when treated with transurethral resection (TURBT)(1) and carcinoma in situ (CIS) has a 54-83% recurrence rate within 4 years(2). Today, the main therapy is intravesical chemotherapy, of which Bacillus Calmette-Guerin (BCG) is the most effective. However, because chemotherapy is only modestly beneficial(3) and most bladder carcinomas will not respond to second course of BCG(4), an additional treatment modality is being researched. Photodynamic therapy (PDT) combines a photosensitizing dye with laser therapy to destroy cancer cells. Pathologic cells take up the photo sensitizing agent and upon activation by visible light (400 - 760 nm) the cancerous cells are destroyed. PDT can be used for focal or diffuse disease. It also can be used to treat recurrent and refractory superficial TCC, in addition to being used as a prophylactic measure. We review the literature (mostly retrospective or nonrandomized studies) that supports the use of PDT for TCC of the bladder. While PDT seems to be a very promising treatment modality, BGC intravesical treatment remains the standard of care for TCC. However if additional randomized trials confirm current data, PDT may soon be a recommendable option.
PurposeWe determined if, before intravesical bacillus-Calmette Guerin (BCG) therapy, p53, p21WAF-1-CIP1 (a critical downstream effector of p53 pathway of cell growth control, inhibiting cyclin dependent kinases) and the cell proliferation marker Ki-67 (MIB-1) could be used as prognostic markers of response to BCG in patients with superficial bladder tumors.
For the past 100 years, tumour immunology has witnessed peaks and troughs of interest. A recent meeting1 covered new technologies and recent developments in the field.
Prostate and bladder carcinoma are, in large part, diseases of older adults, and they are discussed in this context. Pathology, diagnosis, and staging are reviewed. Surgical and medical approaches to these malignancies, and the limitations of these approaches, are highlighted. Renal cell carcinoma, while a relatively rare neoplasm, remains a formidable challenge: approximately 50% of patients die within 5 years of diagnosis. Advances in molecular genetics and histopathologic classification, as well as surgical management and investigational therapies, are emphasized.
• To evaluate the efficacy and toxicity of the combination of bacillus Calmette-Guérin (BCG) and interferon α-2B (IFNα-2B) in treating superficial bladder cancer (SBC). The mentioned combination has shown synergism in pre-clinical studies.
• The present study is a single-arm, open-label, single-institution prospective trial. Patients with Ta, T1 or in situ carcinoma and no previous intravesical therapy were included between July 2002 and June 2009. • Patients were treated with weekly intravesical instillation of 27 mg of BCG mixed with 10 million units (MU) of IFNα-2B for six consecutive weeks followed by 3-weekly booster instillations at 3 months if there was no recurrence. • The primary endpoint was disease recurrence. Secondary endpoints were disease progression and toxicity. • Patients were followed-up with cystoscopy and urine cytology every 3 months.
• In all, 50 patients were included. • At a median follow-up of 55.8 months, 31 (62%) patients were recurrence-free. • Progression to muscle invasion occurred in two (4%) and metastasis occurred in two (4%) patients. • Treatment was well tolerated, with grade III dysuria and frequency occurring in 18 and 14% of patients, respectively, and with 74% of patients being able to complete the maintenance dosage.
• The combination of BCG and IFNα-2B in the patient population with SBC has similar efficacy and toxicity to BCG monotherapy.
Photodynamic therapy (PDT) is an innovative minimally invasive therapy that has great potential for both tumor ablation and normal tissue preservation. However, while in recent years the standards of surgery, radiation and chemotherapy have dramatically improved in terms of outcomes and morbidity, the same cannot be said of PDT in general and Photofrin((R))-based PDT in particular. As currently practiced PDT dosimetry has not really improved tumor ablation and diminished side effects over reports from two decades ago. We critically examine the clinical variables available for PDT dosimetry and conclude that the simple maneuver of diminishing drug dose, with an appropriate increase in light dose, can enhance disease control with a significantly lower risk of morbidity. This conclusion should also be applicable to most systemically introduced photosensitizer.
Arsenic exposure is associated with an increased risk of bladder cancer. To explore the distribution of the arsenic methylation capability and myeloperoxidase (MPO) and sulfotransferase (SULT) 1A1 genotypes in patients at different stages and grades of urothelial carcinoma (UC), 112 UC cases were recruited between September 2002 and May 2004 for this study. Urinary arsenic species, including inorganic arsenic (As(III) + As(V)), monomethylarsonic acid, and dimethylarsinic acid, were determined with a high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. The MPO and SULT1A1 genotypes were examined with polymerase chain reaction and restriction fragment length polymorphism. Differential effects of the arsenic methylation capability were found among patients with different stages of UC; however, urinary arsenic concentrations were borderline significantly increased with the progress of UC patients regardless of whether or not they had been exposed to arsenic from drinking water. The MPO and SULT genetic polymorphisms might modify the arsenic methylation profile and UC progression, and thus are worthy of further investigation.
This study was undertaken to identify differences in protein expression profiles between superficial bladder transitional cell carcinoma (BTCC) and normal urothelial cells. We used laser capture microdissection (LCM) to harvest purified cells, and used two-dimensional liquid chromatography (2D-LC) followed by electrospray ionization-tandem mass spectrometry (ESI-MS/MS) to separate and identify the peptide mixture. A total of 440/438 proteins commonly appeared in 4 paired specimens. Multi-step bioinformatic procedures were used for the analysis of identified proteins; 175/179 of the 293/287 proteins that were specific expressed in tumor/normal cells own gene ontology (GO) biological process annotation. Compared with the entire list of the international protein index (IPI), there are 52/46 GO terms exhibited as enriched and 6/10 exhibited as depleted, respectively. Significantly altered pathways between tumor and normal cells mainly include oxidative phosphorylation, focal adhesion, etc. Finally, descriptive statistics show that the shotgun proteomics strategy has practice directive significance for biomarker discovery by two-dimensional electrophoresis (2-DE) technology.
Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) for sensitization is a promising treatment for carcinoma in situ and diffuse premalignant changes of the bladder. We studied the biodistribution of PpIX in a range of tissues with oral and intravesical routes of administration of ALA and compared the photodynamic effects on bladder and skin.
Normal Wistar rats were given oral or intravesical ALA and PpIX levels in the liver, kidney, skin, and bladder measured by fluorescence microscopy on tissue sections. At the time of maximum PpIX levels, the bladder and skin on the back were illuminated with light at 630 nm and the PDT effects compared.
PpIX fluorescence in the urothelium after 200 mg/kg given intravesically was comparable to that found after 100 mg/kg orally. The ratio of PpIX levels between the urothelium and the underlying muscle was the same for both routes of administration, although there appeared to be more selectivity of urothelial PDT necrosis after intravesical administration. Skin photosensitization was greater after oral ALA, the epidermal PpIX level being three times higher than after intravesical administration for comparable urothelial levels and the PDT effect being more marked.
Intravesical instillation is preferable to oral administration of ALA for PDT ablation of the urothelium of the rat bladder without damage to the underlying tissue layers and for minimizing skin photosensitivity. The technique is now ready for clinical trials.
We evaluate the clinical experience with recombinant interferon-alpha in superficial transitional cell carcinoma and discuss the most rational use of recombinant interferon-alpha in the context of current treatment options.
The available data were reviewed and discussed at a consensus conference in August 1996. The conclusions and recommendations are those of the authors based on the consensus reached at that meeting.
While bacillus Calmette-Guerin (BCG) is recognized as the most efficacious intravesical agent in the prophylaxis and treatment of superficial transitional cell carcinoma, it is associated with significant toxicities and a 20 to 40% relapse rate. Interferons, particularly recombinant interferon-alpha, have demonstrated efficacy against primary and recurrent papillary transitional cell carcinoma and carcinoma in situ with minimal toxicity, although the response and relapse rates are inferior to BCG. Intravesical recombinant interferon-alpha therapy has also produced responses in patients who failed to respond or were refractory to BCG or chemotherapy.
The clinical experience suggests that recombinant interferon-alpha has an important role in the treatment of superficial transitional cell carcinoma, particularly as second line therapy following failure of BCG or chemotherapy, and it may have synergistic effects when combined with chemotherapy or BCG. We propose a prospective randomized study comparing the efficacy of recombinant interferon-alpha, BCG and BCG plus recombinant interferon-alpha as maintenance following complete response to primary BCG therapy. The proposed study would also investigate the efficacy of BCG plus recombinant interferon-alpha as second line therapy following BCG failure. This study will be important to determine the most effective strategy to integrate recombinant interferon-alpha into current treatment options for superficial bladder cancer.
This study correlated biomarkers expressed in tumor and epithelial field with clinical response and recurrence. Of 25 bladder cancer patients, 11 received 6 weeks of intravesical Bacille Calmette-Guerin (BCG), and 14 were treated weekly with intravesical dimethylsulfoxide (DMSO) for 4 weeks to further modulate biomarker expression. G-actin, DNA aneuploidy, and p300 tumor antigen were evaluated by quantitative fluorescence image analysis on uroepithelial cells from bladder wash samples prior to and immediately following treatment. Excluding patients who did not respond to BCG (and who had persistently abnormal p300 and DNA markers), recurrence correlated with persistent abnormal G-actin findings. Of patients who were G-actin negative following therapy, only 25% recurred during follow-up in contrast to 67% in patients who were positive (p < 0.03 by Fisher's exact test). The odds ratio for recurrence was 6.00 (95% confidence interval: 1.3-28.6). Cytosolic G-actin levels can be an important intermediate end point marker for chemoprevention.
Intravesical immunotherapy with bacillus Calmette-Guerin (BCG), which has become the gold standard in the adjuvant treatment of superficial bladder cancer, is hampered by local side effects. Anti-inflammatory drugs may be helpful, but as an undesired side effect, therapeutic efficacy of BCG might be impaired. Therefore, we investigated the effects of anti-inflammatory drugs on the efficacy of intravesical BCG in an animal model.
Syngenic tumor cells were implanted into the bladders of 75 mice according to our modification of the method. Mice were randomized to 5 groups with 15 animals each and treated with phosphate buffered saline (PBS), group 1; BCG, group 2; BCG + acetylic salicylic acid (ASA), group 3; BCG + pentoxifylline (POF), group 4; autoclaved BCG (aBCG), group 5. Intravesical instillation of 1.35 mg. BCG was initiated one day after tumor inoculation and repeated in weekly intervals for 4 instillations altogether. ASA and POF in doses of 200 mg./kg. and 150 mg./kg., respectively, were given continuously with the drinking water starting at the first instillation. Autoclaved BCG served as control for the importance of viability and was given at the same dose as viable BCG. Mice were monitored for survival, gross hematuria and body weight and after 28 days evaluated for bladder weight and tumor occurrence.
Autoclaved BCG and PBS had no effect on tumor growth, whereas animals treated with viable BCG alone and in combination with POF and ASA, respectively, showed a significant reduction in bladder weight: PBS, 248 mg.; BCG, 140 mg. (p = 0.0009); BCG + ASA, 123 mg. (p = 0.0001); BCG + POF, 145 mg. (p = 0.0004); autoclaved BCG, 283 mg. (p = 0.21). Mice treated with BCG, BCG + ASA and BCG + POF showed a significantly higher proportion of survival until day 28 as compared to PBS alone. Autoclaved BCG had no therapeutic efficacy (Kaplan-Meier method/log rank test: BCG, p = 0.0053; BCG + ASA, p = 0.0044; BCG + POF, p = 0.0027; aBCG, p = 0.33). No significant differences among the 3 groups treated with viable BCG, with or without anti-inflammatory drugs, regarding bladder weight and survival were detectable.
The efficacy of BCG therapy in murine orthotopic bladder cancer is dependent on BCG viability and is not compromised by ASA or POF. Clinical trials to evaluate the efficacy of routine ASA or POF to reduce BCG side effects in patients, using self-assessment criteria, should be initiated.
Valrubicin (AD-32) is an N-trifluoroacetyl, 14-valerate derivative of the anthracycline doxorubicin. It has antineoplastic activity which probably results from interference with nucleic acid metabolism by the drug.
▲ Valrubicin entered individual cells more rapidly than doxorubicin in vitro. When valrubicin was administered intravesically to patients with bladder cancer, cytotoxic concentrations of the drug penetrated the superficial muscle layer of the bladder.
▲ Complete response rates were 18 and 29% in patients with carcinoma in situ of the bladder which was refractory to intravesical BCG in 2 non-comparative trials of prophylactic intravesical valrubicin. In patients with recurrent superficial papillary tumours, the complete response rate was 46%.
▲ Adverse events were generally transient in patients who received intravesical valrubicin. Bladder irritation occurred in 88% of patients. Systemic absorption of intravesically administered valrubicin was minimal. Accordingly, systemic adverse events generally occurred in ≤5% of patients.
▲ Valrubicin was less toxic to chick embryos and haematopoietic stem cells in vitro and produced a lower incidence of cardiotoxicity in rabbits, compared with doxorubicin.
Calphostin C, a highly specific protein kinase C inhibitor, induces apoptosis in the presence of visible light. We report the photoactivatable cytotoxicity of calphostin C in a series of well-characterized human bladder cancer cell lines: RT4, UM-UC-3, and 5637.
The human bladder cancer cell lines RT4, UM-UC-3, and 5637 were chosen on the basis of their p53, pRb and 9p21 deletion status. Using standard tissue culture techniques, the cytotoxicity of 10 to 100 nM calphostin C in combination with increasing exposures of visible light was examined. Controls consisted of cells treated with calphostin C without visible light and cells exposed to visible light without calphostin C treatment. Cell viability was determined by MTT assay. The induction of apoptosis by activated calphostin C was determined by 4,6-diamidino-2-phenylindole (DAPI) staining/fluorescence microscopy of nuclei.
In the absence of light, calphostin C did not demonstrate a cytotoxic effect on any of the cell lines tested. Increasing the duration of light exposure resulted in a concomitant decrease in cell viability. Significant cell death was seen with calphostin C concentrations as low as 10 nM. These studies also demonstrated that calphostin C induced apoptosis by a mechanism independent of p53 and pRb status and the presence or absence of 9p21 deletions.
We demonstrated the ability of activated calphostin C to induce apoptosis in a light-dependent and concentration-dependent fashion in a bladder cancer model system. Activated calphostin C cytotoxicity is independent of tumor genetic background and the status of p53 and pRb. Further development of calphostin C as a photosensitizer for photodynamic therapy of superficial bladder cancer may be warranted.
Twenty-one multifocal urinary tract transitional cell carcinomas, mostly bladder tumours, from a total of six patients were processed for cytogenetic analysis after short-term culturing of the tumour cells. Karyotypically related, often identical, cytogenetically complex clones were found in all informative tumours from each case, including the recurrent tumours. Rearrangement of chromosome 9, leading to loss of material from the short and/or the long arm, was seen in all cases, indicating that this is an early, pathogenetically important event in transitional cell carcinogenesis. The presence of related clones with great karyotypic similarity in anatomically distinct tumours from the same bladder indicates that multifocal uroepithelial tumours have a monoclonal origin and arise via intraluminal seeding of viable cancer cells shed from the original tumour. Later lesions may develop also from cells shed from the so called second primary tumours. The relatively complex karyotypes seen in all lesions from most cases argue that the seeding of tumour cells is a late event that succeeds the acquisition by them of multiple secondary genetic abnormalities.
The effect of intravesical instillation of doxorubicin or epirubicin after transurethral resection (TUR) was estimated from the data of five randomized clinical trials in Japan. The authors provided the estimated hazard function plots with a smoothing technique, to evaluate the prophylactic effect of an intravesical therapy over time and to estimate the natural history of superficial bladder carcinoma.
Data on a total of 1732 patients from 5 studies of the Japanese Urological Cancer Research Group who were eligible to receive doxorubicin and epirubicin were analyzed. The patients were divided into four subgroups based on their background characteristics. Their tumors were categorized as "primary and solitary," "primary and multiple," "recurrent and solitary," or "recurrent and multiple."
Multivariate analysis revealed that intravesical instillation reduced the risk of recurrence to about one-half to two-thirds compared with the controls. The shapes of the graphs that estimated the hazard function for patients with no prophylaxis indicated that multiple tumors showed an earlier peak of recurrence than solitary tumors and recurrent tumors had a higher hazard of recurrence than primary tumors. Graphic presentation of the hazard function in each subgroup suggested that the effect of prophylaxis continued for 500 days after TUR but not for longer.
This analysis indicated that there are two patterns of tumor recurrence of superficial bladder carcinoma after TUR, namely, early phase and late phase. Intravesical chemotherapy may be effective mainly in reducing the hazard for recurrence in the early phase.
Unlabelled:
The anthracycline epirubicin has been investigated for intravesical use in patients with superficial bladder cancer. In multicentre, randomised trials, prophylaxis with intravesical epirubicin 30 to 80 mg after transurethral resection (TUR) was more effective than no prophylaxis in the prevention of disease recurrence. Intravesical prophylaxis with epirubicin was as effective as that with equivalent dosages of doxorubicin after TUR. Data are conflicting concerning the relative efficacy of intravesical epirubicin and bacillus Calmette-Guerin (BCG) in patients at intermediate risk of recurrence after TUR, but epirubicin was less effective than BCG in those at high risk. The efficacy and tolerability of prophylaxis with epirubicin relative to that with mitomycin is not yet established. The efficacy of epirubicin as prophylaxis after TUR in combination with BCG or interferon-alpha-2b, or as treatment in patients with superficial bladder cancer has been evaluated in small, noncomparative trials, but requires clarification. Adverse events associated with intravesical epirubicin were generally mild and transient. The most common adverse events were localised to the bladder (cystitis, haematuria and urinary tract infection). Systemic adverse events (cardiac, haematological or related to hypersensitivity) were not reported in many trials of intravesical epirubicin, and when reported generally occurred in < or =5% of patients who received the drug. Intravesical epirubicin was generally tolerated as well as intravesical doxorubicin and was associated with a lower incidence of mild chemical cystitis in 1 clinical trial. The incidence of adverse events associated with intravesical epirubicin was markedly lower than that associated with intravesical BCG.
Conclusions:
Intravesical epirubicin has shown efficacy in preventing disease recurrence after TUR of superficial bladder cancer. In comparison with equivalent dosages of doxorubicin, the efficacy of epirubicin for this indication is generally similar, and the tolerability profile may be more favourable. Epirubicin is less effective than BCG as intravesical prophylaxis in patients at high risk of recurrence after TUR; the relative efficacy of epirubicin and BCG after TUR in patients at intermediate risk is not yet clear. Intravesical epirubicin is generally tolerated better than BCG. Intravesical epirubicin may be used as prophylaxis after TUR in patients who are at low or intermediate risk of recurrence of superficial bladder cancer.
Keyhole limpet hemocyanin (KLH) is a nonspecific immunomodulator, demonstrated to be clinically effective in superficial bladder cancer. The present study investigated the clinical efficacy of intravesical KLH in patients with carcinoma in situ (CIS) with a long-term follow-up.
Thirteen patients with CIS grade III were treated with intravesical instillations of KLH, 20 mg for 6 weeks, then monthly for 1 year and bimonthly for 2 subsequent years. Patients not responding to 2 courses of KLH were treated with bacillus Calmete-Guérin (BCG, 81 mg Connaught strain).
The follow-up period ranged from 12 to 84 months. Two patients were free of tumor after KLH instillations with a follow-up of 66 and 82 months, respectively. All patients who did not respond to the primary KLH course, but to the 'rescue' instillation of BCG, experienced recurrences after 42, 48, 56 and 60 months after the first KLH instillation treatment. Three patients with recurrent CIS and who were not cystectomized had recurrences after prolonged remission (4-5 years). Patients progressing despite KLH and BCG instillations underwent cystectomy.
KLH demonstrates efficacy and induces long- term remissions against CIS in a limited number of cases. In the present study, most patients with CIS progressed over time whatever the substance instilled, whether KLH or BCG. CIS remains a very aggressive neoplasm requiring a lifelong follow-up. Further studies are necessary to define the precise role of KLH in patients with CIS.
For more than 20 years, superficial bladder tumors have been demonstrated to be sensitive to several biological response modifiers and especially to immunomodulators. The best-known and studied immunomodulator is the bacillus Calmette-Guérin (BCG). However, despite its well-recognized efficacy, BCG is not a universal panacea and is associated with potentially significant side effects.
New perspectives in BCG therapy aiming to increase BCG efficacy or to decrease side effects include the use of genetically engineered BCG strains producing cytokines as well as the use of purified BCG subcomponents. Because a cascade of immunological reactions including the secretion of several cytokines has been demonstrated in the BCG mode of action, many other biological response modifiers and especially immunomodulators have been studied for superficial transitional cell carcinoma therapy. Some were investigated in human trials, others are still in laboratory studies; some are administered intravesically whereas others are given orally. Interferon-alpha (IFN-alpha) intravesical instillations have been evaluated in several controlled studies.
Although toxicity of intravesical IFN is minimal, its optimal dose, schedule and efficacy remain to be defined. Recent prospective studies comparing IFN to BCG intravesical therapy have been somewhat disappointing although this cytokine may be effective in some patients with T(a)-T(1) disease who have failed BCG therapy. Other immunomodulators administered intravesically investigated in clinical studies include interleukin 2 (recently used in a clinical study with a marker tumor response), levamisole, Rubratin, a Nocardia rubra cell wall skeleton, and keyhole limpet hemocyanin. Several biological response modifiers administered orally such as vitamin A (and its derivatives), Lactobacillus casei or bropirimine have been tested in clinical trials as well. In contrast, Allium sativum (garlic) or OK-432 (a streptococcal preparation) or BCG subfractions have been tested in laboratory studies only.
Published reports on several of these biological response modifiers suggest that these compounds may be an alternative in patients with superficial bladder cancer who have failed or have not tolerated BCG, but further evaluation to improve efficacy, durability and understand their mechanism of action is warranted.
To evaluate the feasibility, efficacy, and toxicity of antegrade chemotherapy delivered continuously as adjuvant treatment for patients with upper tract transitional cell carcinoma.
During a 6-year interval, 12 patients with upper tract transitional cell malignancies underwent continuous antegrade intraluminal infusion chemotherapy (CAIIC) with adriamycin. After placement of percutaneous access and surgical treatment of the primary lesion, patients received 5-day cycles of CAIIC. Patients received between two and four treatment cycles at 2-week intervals. After therapy, patients with no evidence of residual disease were then monitored long-term with retrograde pyelography and upper tract cytology.
Twelve patients underwent a total of 35 5-day cycles of CAIIC. No patient experienced hematologic and/or local/regional toxicity during or after drug infusion. Three patients were treated for upper tract carcinoma in situ, and 9 patients had discrete exophytic tumors. Two patients died (treatment unrelated) before a final assessment of therapeutic outcome, leaving 10 patients available for evaluation of the therapeutic response. One patient with carcinoma in situ and 5 of 7 patients with discrete upper tract tumors remained disease free after surgery and adjuvant therapy. Both patients with discrete tumors in whom therapy failed had residual gross disease after primary surgical treatment.
CAIIC using adriamycin was well tolerated for periods of up to 5 days over multiple cycles. Early data suggest a limited efficacy in treating patients with gross residual disease. The efficacy of this approach in preventing the recurrence of upper tract disease after surgical ablation awaits further assessment.
Evaluate the efficacy and toxicity of alternating intravesical instillation of Bacillus Calmette-Guerin(BCG) and Interferon alpha2-b (IFN) in the treatment and prevention of recurrence of superficial transitional cell carcinoma (TCC) of the urinary bladder.
Patients with Ta, T1 tumors and carcinoma in situ, either recurrent (TaG1, T1G1) or primary/recurrent TaG2 TaG3, T1G2, T1G3 and Tis (T: Tumor stage, G: grade) are eligible. All patients received intravesical BCG 81 mg on Weeks 1, 3, 5 and 7 and IFN 100 million units on Weeks 2, 4, 6 and 8. Cystoscopy performed 4 weeks after completion of therapy, and every 3 months thereafter.
There was a total of 37 patients. Thirteen had TaG2, 13 T1G2, 1 T1G1, 4 TaG1, 1 TaG3, 3 T1G3 and 7 Tis (5 concurrent with other above tumors). Index lesion cleared in 7/10 patients. With a median follow-up of 26.2 month, 22 patients (59%) failed above therapy. Median time to treatment failure was 7 months. Seven, 6 and 9 patients recurred at a higher, lower and same stage or grade respectively. No grade 3 or 4 toxicity was encountered.
Alternating intravesical BCG and IFN is effective and well tolerated therapy for superficial TCC of urinary bladder.
Coupling of photosensitizers to tumor-selective monoclonal antibodies (MAbs) is an attractive option for improving the selectivity of photodynamic therapy (PDT). For this purpose, hydrophilic sensitizers would be most suitable because of their solubility in water. However, such sensitizers are known to be ineffective in PDT, probably because they cannot readily pass the cell membrane and reach the critical intracellular target. We used the model compound TrisMPyP-PhiCO(2)H, a hydrophilic porphyrin derivative, to test the hypothesis that hydrophilic photosensitizers might become of therapeutic value when directed into the tumor cell by use of internalizing MAbs. TrisMPyP-PhiCO(2)H was conjugated using a labile ester. Conjugates showed no impairment of integrity on SDS-PAGE, full stability in serum in vitro, and optimal immunoreactivity when the sensitizer:MAb ratio was </=3. At higher molar ratios, the solubility of the conjugates decreased. In vitro internalization experiments showed that TrisMPyP-PhiCONH-(125)I-cMAb U36 and TrisMPyPPhiCONH-(125)I-mMAb 425 conjugates were internalized by A431 cells, in contrast to TrisMPyP-PhiCONH-(125)I-mMAb E48 conjugates. Data on the in vitro efficacy of PDT with MAb-conjugated TrisMPyP-PhiCO(2)H showed that the internalizing cMAb U36 and mMAb 425 conjugates were phototoxic to A431 cells, while the non-internalizing E48 conjugate and the unconjugated sensitizer were not. Biodistribution data of conjugates with sensitizer:(125)I-cMAb U36 ratios varying from 1:1 to 3:1 in tumor-bearing nude mice revealed selective accumulation in the tumor. Conjugates with higher molar ratios were cleared more rapidly from the blood than the unconjugated (125)I-cMAb U36, resulting in lower tumor uptake but similar tumor-to-blood ratios. Our data suggest that hydrophilic photosensitizers might have therapeutic value when targeted to tumors by internalizing MAbs.
Photodynamic therapy (PDT) produces localized necrosis with light after prior administration of a photosensitizing drug. The problems with laser light dosimetry and complications relating to bladder function appear to be important limiting factors of PDT in urology. Photodynamic therapy on urinary bladder with normal epithelium of rats was performed using an argon ion laser as an energy source, with aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) photosensitizer. Four hours after ALA intravenous administration, the bladders were intravesically radiated with light doses 20, 40, or 80 J/cm2. Animals in the control group did not receive ALA and were radiated with 20 J/cm2 light dose. Three weeks prior to PDT, the bladder capacity and pressure changes during filling cystometry were assessed. Cystometrics were repeated 1, 3, 7, or 21 days after laser therapy. The light dose 20 J/cm2 and 40 J/cm2 together with the used ALA dose caused no reduction in bladder capacity, whereas 80 J/cm2 light dose produced up to 50% reduction in the capacity at 3 weeks postoperatively. In control group without ALA, the animals did not regain more than 34% of the capacity of their control values at 3 weeks. The light dose of 20 J/cm2 and 40 J/cm2 with ALA induced functional changes that subsided after day 1. Our results indicate that with proper dosing of photosensitizing drug and light energy, the functional impairment of urinary bladder may be reduced as transient. These findings support the use of PDT as safe therapy of superficial bladder cancer.
Influence of dispersions of mucoadhesive polymers chitosan and polycarbophil on permeability properties of urinary bladder was investigated in vitro on isolated porcine urinary bladder. Pipemidic acid as a model hydrophilic drug was used. Its distribution in the bladder wall was determined from actual tissue concentrations by a method based on sectioning of frozen tissue and extraction of tissue slices. Pipemidic acid tissue concentration versus tissue depth profiles were evaluated by a diffusion model assuming constant diffusion coefficient. Increase in bladder wall permeability was observed in the presence of both polymers. Apparent permeability (mean+/-S.D.) of urinary bladder wall was increased 2.7+/-2.9 and 2.8+/-2.0 times for chitosan, and 2.3+/-2.0 and 4.3+/-4.2 times for polycarbophil at 0.5 and 1.0%, w/v polymer concentration, respectively. This increase is a consequence of the increased permeability of urothelium. These findings support investigations on application of chitosan and polycarbophil in development of mucoadhesive intravesical drug delivery systems. Experimental model may be applied to evaluate the results of experiments with drugs used in intravesical therapy.
Bacillus Calmette-Guérin (BCG) and interferon-alpha2B (IFN-alpha2B) have both been individually used for the intravesical treatment of superficial bladder cancer. We report our experience on the therapeutic efficacy and toxicity of combined intravesical BCG plus IFN-alpha2B for treating superficial bladder cancer, including patients failing previous BCG therapy. Thirty-two patients with superficial bladder cancer underwent 6 weekly treatments with full-, one-third, or one-tenth-dose of BCG plus 50 or 100 MU of IFN-alpha2B based on prior BCG exposure and tolerance. Patients with no evidence of disease proceeded onto maintenance therapy of 3 weekly treatments at 3 months followed by 2 additional maintenance cycles given 6 months apart. Response was assessed by cystoscopy/biopsy every 3 months after treatment. Before BCG plus IFN-alpha2B treatment, 20 patients (63%) had previously failed intravesical BCG therapy, 27 (84%) had aggressive disease (stage T1, grade 3, or carcinoma in situ), 27 (84%) had recurrent disease, 14 (44%) had multifocal disease, and 6 (19%) had disease of over 4 years duration. At median follow-up of 22 months, 21 patients (66%) remain disease-free and 11 patients (34%) had disease-recurrence. Nineteen of 32 patients (59%) were disease-free after the initial induction cycle. Six of 11 patients 55% ultimately failing combination therapy did so at the first 3 to 4 month evaluation. Four of 7 patients (57%) benefited from salvage re-induction therapy. Of the 20 patients previously treated with BCG, 12 patients (60%) remain disease-free. Combination BCG plus IFN-alpha2B intravesical therapy was well tolerated. Combination intravesical BCG plus IFN-alpha2B is an effective and tolerable alternative for patients with superficial bladder cancer, including those patients in whom intravesical BCG therapy had previously failed. Benefits of this combination therapy may include potentially less morbidity, improved clinical efficacy, and in the long term, fewer patients undergoing radical therapy. However, radical treatment options should be pursued for early failures of this combination regimen in those patients with risk factors for recurrence and progression.
Hypericum perforatum L. (St. John’s wort) is a medicinal plant used for many pathologies, especially for the treatment of mild to moderate depression. In the present study we have investigated the cytotoxic activity of the locally collected (Epirus region) Hypericum perforatum L. against cultured T24 and NBT-II bladder cancer cell lines. The lipophilic extract of the herb, prepared using petroleum ether, induced apoptosis displaying LC50 values at concentrations as low as 4 and 5 μg/mL. A fraction of this extract displayed 60 % cell growth inhibition at a concentration of 0.95 μg/mL. Evaluating the importance of various biologically active components of the extract, it was found that hypericins (hypericin, pseudohypericin, etc.) were identified only in the methanolic (lipophobic) extract of the herb, and not in the active lipophilic extract. In addition, hyperforin concentrations in the lipophilic extract and its most active fraction, were 0.94 μg/mL, and 0.17 μg/mL, respectively, while the active cytotoxic concentration of pure hyperforin appeared in the range of 1.8 μg/mL - 5.0 μg/mL. Therefore, pure hyperforin does not seem to contribute significantly to the cytotoxicity activity. Chlorophylls were identified in low, not significantly different, concentrations in all extracts and fractions and were not correlated to the biological activity.
Owing to the combination of significant cytotoxic activity, natural abundance and low toxicity, the lipophilic extract of Hypericum perforatum holds the promise of being an interesting, new, antiproliferative agent against bladder cancer that deserves further investigation.
Abbreviations
HP:Hypericum perforatum L.
AS:aqueous solution
MS:methanolic solution
ME:methanolic extract
NPMF:non polar methanolic fraction
PMF:polar methanolic fraction
PEE:petroleum ether (lipophilic) extract
PEE (1,2,3,4,5,6,7):petroleum ether extract's fractions
PBS:phosphate buffered saline
DMSO:dimethyl sulfoxide
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