Novel therapeutics in the treatment of bladder cancer.
ABSTRACT The successful treatment of bladder cancer remains a challenge for urologists and oncologists. There have been substantial changes in the therapeutic options for the management of both superficial and muscle-invasive bladder cancer in the last 5 years. Here we review the preclinical and clinical developments over the last year in bladder cancer therapeutics.
There is a growing trend toward the use of multimodal treatments for all bladder cancers. For superficial disease, intravesical instillation of chemotherapeutic agents after transurethral resection is quickly becoming the standard of care. Novel therapeutic modalities under investigation include DNA vaccines, magnetically targeted carriers, bio-adhesive microspheres and antisense oligodeoxynucleotides. For muscle-invasive bladder cancer, systemic perioperative chemotherapy is being used with increasing frequency and the latest preclinical research efforts are focused on the inhibition of angiogenesis and other processes predisposing to metastatic disease.
Treatment goals for bladder cancer of any stage are complete removal of the initial tumor, prevention of disease recurrence and effective inhibition of progression to advanced disease with the ultimate aim of reducing mortality. The myriad novel therapeutic modalities currently being explored suggest that these goals may perhaps be achievable within our lifetime.
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ABSTRACT: Inhibitors of endothelial cell proliferation, such as endostatin, result in suppression of tumor-associated angiogenesis and can achieve growth-inhibitory effects depending on the type of tumor treated. The purpose of this study was to investigate whether local overexpression of endostatin could serve to diminish tumor growth of bladder cancer in vivo. We examined the capability of lentiviral-mediated gene transfer in vitro and therapeutic effects of lentivirus-based vectors expressing endostatin on tumor growth using an orthotopic human bladder tumor model. We found that self-inactivating lentivirus vectors containing green fluorescent protein, alone or in combination with endostatin, were capable of efficient and stable gene transfer to a variety of human bladder tumor cell lines. The production and secretion of endostatin from lentivirus-transduced KU-7 human bladder cancer cells was confirmed by Western blot and competitive enzyme immunoassay. Intravesical instillation of untransduced, green fluorescent protein control lentivirus-transduced, and endostatin-transduced KU-7 cells was performed in murine models to establish orthotopic tumors. Sustained long-term expression of endostatin was achieved in lentivirus-transduced orthotopic bladder tumors, and it was associated with decreased vascularization and inhibition of tumor growth. Lentivirus vector-mediated overexpression of endostatin did not affect the intrinsic production of basic fibroblast growth factor and vascular endothelial growth factor. These findings suggest that lentivirus-mediated gene transfer might represent an effective strategy for expression of angioinhibitory peptides to achieve inhibition of human bladder cancer proliferation and tumor progression.Clinical Cancer Research 04/2004; 10(5):1835-42. · 7.84 Impact Factor
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ABSTRACT: We aimed to promote the efficacy of paclitaxel in intracavitary treatment of superficial transitional cell carcinoma of the bladder by designing bio-adhesive microspheres capable of achieving controlled release of the drug at the urothelium/urine interface. Poly(methylidene malonate 2.1.2) microspheres encapsulating paclitaxel were prepared by a single emulsion method. Bioactivity of the released paclitaxel was confirmed by assessing cytotoxicity on MBT-2, a bladder cancer cell line. Biodistribution of particles after bladder instillation was assessed by confocal microscopy and scanning electron microscopy. In vivo studies were performed in Balb/c mice after bladder cancer was induced by BBN (N-n-Butyl-N-butan-4-ol-nitrosamine) in drinking water. The efficacy of intravesical injections of conventional and microsphere paclitaxel was assessed by histology and survival rates. Spherical 5 microm microspheres with 5% weight per weight paclitaxel loading ensured sustained release of bioactive paclitaxel. After bladder instillation the microspheres adhered to the mucosa and remained in the bladder lumen for at least 48 hours. In the BBN induced bladder cancer model compared with controls the 9-week survival rate was significantly improved by 2 injections of paclitaxel bio-adhesive microparticles. Microscopic evaluation confirmed the lower incidence of carcinoma in situ and high grade transitional cell carcinoma after injections of paclitaxel bio-adhesive microparticles compared with controls and with injections of similar doses of the conventional paclitaxel formulation. Intravesical administration of poly(methylidene malonate 2.1.2) paclitaxel microspheres is a promising approach for intracavitary chemotherapy of superficial bladder cancer.The Journal of Urology 04/2004; 171(3):1324-9. · 3.70 Impact Factor
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ABSTRACT: We determined whether combining low dose bacillus Calmette-Guerin (BCG) interferon-alpha 2B would be effective for patients in whom previous BCG failed. A total of 40 patients in whom 1 (19) or more (21) previous induction courses of BCG failed received 6 to 8 weekly treatments of 1/3 dose (27 mg.) BCG plus 50 million units interferon-alpha 2B. Additional 3 week miniseries of further decreased BCG (1/10, 1/30 or 1/100) titrated to symptoms without changing the interferon-alpha 2B dose were given at 5, 11 and 17 months. In 12 patients a second induction course was given with 1/10 BCG plus 100 million units interferon-alpha 2B. There was multifocal disease in 39 patients, previous BCG had failed within 6 months in 34, disease was aggressive (stage T1, grade 3 or carcinoma in situ in 31, there had been 2 or more previous recurrences in 25 and disease history was greater than 4 years in 13. At a median followup of 30 months 63% and 53% of patients were disease-free at 12 and 24 months, respectively. Patients in whom 2 or more previous BCG courses had failed fared as well as those with 1 failure. Of the 18 failures 14 occurred at the initial cystoscopy evaluation. Of 22 patients initially counseled to undergo cystectomy 12 (55%) are disease-free with a functioning bladder. Combination therapy was well tolerated. While longer followup and larger multicenter studies are required to validate these encouraging findings, intravesical low dose BCG plus interferon-alpha 2B appears to be effective in many cases of high risk disease previously deemed BCG refractory. However, early failure while on this regimen should be aggressively pursued with more radical treatment options.The Journal of Urology 11/2001; 166(4):1300-4, discussion 1304-5. · 3.70 Impact Factor