Cisplatin bladder cancer

Fig. 7. Effect of light on the IC50 values for the inhibition of cell growth of various cancer cell lines by platinum(IV) diazido complexes, (a) toxicity of the cis-complexes 4 and 5 on human bladder cancer cell lines (5637-CDDP, cisplatin-resistant cell line) (b) comparison of cytotoxicities of the cis- and rarcs-isomers 4 and 6 in the dark and upon irradiation cisplatin is included for comparison. Data from Ref. (30).

Bristol-Myers Squibb Co. (Bristol) distributes cisplatin (known by the brand names of Platinol and Platinol-AQ ), which is approved for treatment of testicular, ovarian and bladder cancer. Bristol s patent listings in the Orange Book and related patent infringement suits demonstrate that doublepatenting and lengthy pendency of a patent application can generate an automatic 30-month stay on FDA approval of generic products close to their otherwise expected approval date. 

These studies were followed by others that demonstrated the potential for therapeutic enhancement by combined cisplatin-radiation treatments with primary murine bladder cancer (60), EMT-6 mammary tumors and KHT and RIF-1 sarcomas (61), and Lewis lung carcinoma (62). 

Early clinical studies clearly demonstrated that cisplatin could be administered safely and concurrently with radiation therapy (73-75). Early clinical trials that demonstrated the promise of the combination of cisplatin and radiation therapy included the treatment of brain tumors (76,77), head and neck tumors (78), malignant melanoma (79), and bladder cancer (80). Early clinical trial integrating carboplatin administration with radiation therapy was carried out in patients with locally advanced nonsmall cell lung cancer (NSCLC) (81). A hypothesis put forth by Coughlin and colleagues (81) was that the best clinical outcomes would be achieved with the combination of cisplatin and radiation therapy in tumors that were responsive to cisplatin. 

Herr HW, Yagoda A, Batata M, Sogani PC, Whitmore WF. Planned preoperative cisplatin and radiation therapy for locally advanced bladder Cancer. Cancer 1983 52 2205-2208. 

Kaufman DS, Winter KA, Shipley WU, et al. The initial results in muscle-invading bladder cancer of RTOG 95-06 phase Ell trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil fohowed by selective bladder preservation or cystectomy depending on the initial response. The Oncologist 2000 5 471 —476. 

Coppin CM, Gospodarowicz MK, James K, et al. Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1996 14(ll) 2901-2907. 

RTOG 9906. A Phase I/II Trial in Patients with Muscle-Invading Bladder Cancer of Transurethral Surgery Plus Taxol, Cisplatin and BID Irradiation Followed by Either Selective Bladder Preservation or Radical Cystectomy and Adjuvant Chemotherapy. Study Protocol. 

Roth BJ, Bajorin DF. Advanced bladder cancer the need to identify new agents in the post-M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) world. J Urol 1995 153 894-900. 

Medical Research Council Advanced Bladder Cancer Working Party. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer a randomised controlled trial. Lancet 1999 354 533-540. 

Shipley WU, Coombs LJ, Einstein AB, Soloway MS, Wajsman Z, Prout GR. Cisplatin and full dose irradiation for patients with invasive bladder cancer a preliminary report of tolerance and local response. J Urol 1984 132 899-903. 

Sauer R, Dunst J, Altendorf-Hofmann A. Radiotherapy with and without cisplatin in bladder cancer. Int J Rad Oncol Biol Phys 1990 19 687-690. 

Chauvet B, Brewer Y, Felix-Faure C, Davin J-L, Choquenet C, Reboul F. Concurrent cisplatin and radiotherapy for patients with muscle-invasive bladder cancer who are not candidates for radical cystectomy. J Urol 1996 156 1258-1262. 

Angulo JC, Sanchez-Chapado M, Lopez JI, Flores N. Primary cisplatin, methotrexate and viblastine aiming at bladder preservation in invasive bladder cancer multivariate analysis on prognostic factors. JUrol 1996 155 1897-1902. 

Neo-adjuvant chemotherapy for muscle invasive and locally advanced bladder cancer has been assessed in a number of randomized studies. Most studies have been relatively small and therefore underpowered. More recently the larger INT 0080 trial from the United States and the MRC/FORTC study from Europe reported survival advantages for neoadjuvant MVAC and CMV but these differences did not quite reach statistical significance. A Cochrane Review (see Advanced Bladder Cancer Overview, 2004) concluded that cisplatin based neo-adjuvant chemotherapy provided a 5% 5-year survival benefit. 

Cisplatin Forms intrastrand and interstrand DNA cross-links binding to nuclear and cytoplasmic proteins Non-small cell and small cell lung cancer, breast cancer, bladder cancer, gastroesophageal cancer, head and neck cancer, ovarian cancer, germ cell cancer Nausea and vomiting Nephrotoxicity, peripheral sensory neuropathy, ototoxicity, nerve dysfunction... 

Cisplatin has major antitumor activity in a broad range of solid tumors, including non-small cell and small cell lung cancer, esophageal and gastric cancer, head and neck cancer, and genitourinary cancers, particularly testicular, ovarian, and bladder cancer. When used in combination regimens with vinblastine and bleomycin or etoposide and bleomycin, cisplatin-based therapy has led to the cure of nonseminomatous testicular cancer. 

Larotaxel (XRP-9881, RPR 109881A) 59 (Sanofi-Aventis) is undergoing Phase III trials in patients with advanced pancreatic cancer who had been previously treated with gemcitabine, as well as in combination with cisplatin to treat locally advanced/metastatic urothelial tract or bladder cancer.124 A Phase III trial for the treatment of advanced breast cancer has been completed. Larotaxel 59129>130 js a semi-synthetic derivative of 10-deacetyl baccatin III with a docetaxel-like side chain that has a low affinity for the P-glycoprotein drug efflux pump, an efflux mechanism that diminishes the effectiveness of the marketed drugs paclitaxel 60 and docetaxel. Importantly, this low affinity should enable larotaxel 59 to be effective in tumours resistant to paclitaxel 60... 

Cisplatin, an alkylating agent, is indicated as an adjunctive therapy in metastatic testicular cancer adjunctive therapy in metastatic ovarian cancer, head and neck cancers, lung cancer, and esophageal cancer, and in the treatment of advanced bladder cancer (see also Figure 15). 

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