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Intravesical and Systemic Chemotherapy of Murine Bladder Cancer¹

Department of Urology, University of Tennessee Center for the Health Sciences, Memphis 38163, and Veterans Administration Hospital, Memphis, Tennessee 38104

Transitional cell carcinomas induced in syngeneic mice by the carcinogen N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) resemble their human counterpart both grossly and histologically and have been used in an animal model to evaluate antitumor drugs for activity in bladder cancer. In C3H/He mice, the first tumors are seen after 8 months on FANFT and an incidence of 70 to 100% is observed by 11 months. In the first of two long-term studies, single or combination chemotherapy was initiated after 10 months of FANFT. The drugs were administered for 3 weeks. Each treatment regimen was capable of producing a significant reduction in the mean bladder weight when compared to a group not receiving therapy (108 mg): cyclophosphamide (CY) (42.9); dactinomycin (49.6); cis-diamminedichloroplatinum(II) (56.4); and Adriamycin (69.5). The combination of CY with Adriamycin (37.3) or 5-fluorouracil (38.3) was superior to CY alone. In the second long-term study using this autochthonous tumor model, identical therapeutic regimens were initiated earlier in the carcinogenic process, after 5 or 7 months on FANFT. The regimens were: CY, 75 mg/kg; Adriamycin, 3 mg/kg, 2 times/week; CY + 5-fluorouracil, 45 mg/kg; CY + Adriamycin, 5 mg/kg; and Bacillus Calmette-Guérin 1 x 10⁷ organisms. CY effected a significant reduction in the mean bladder weight, 30.8 mg at 5 months and 42.1 mg at 7 months (control, 44.6; p < 0.001 and < 0.05). The combination of CY with 5-fluorouracil and Adriamycin was superior to CY alone. Mice receiving Bacillus Calmette-Guérin for either 3.5 or 5.5 months had a significant increase in the size of resulting tumors as indicated by the mean bladder weight.

Intravesical chemotherapy was also evaluated by determining which drugs were capable of inhibiting the implantation of transitional tumor cells. A single-cell suspension of a transplantable FANFT-induced tumor is capable of implanting on the denuded murine urothelium. Since tumor cell implantation might be a factor in the high recurrence rate of human bladder cancer, irrigation with an effective cytotoxic agent might reduce this incidence. Intravesical Epodyl and epipodophyllotoxin significantly reduced the incidence of tumor cell implantation in the animal model. Thiotepa exhibited moderate antitumor activity.

It is hoped that information gained from these animal models, which allow evaluation of many drugs within a relatively short period of time, will identify drugs effective in transitional cell carcinoma and lead to therapeutic trials in patients with bladder cancer.

¹ Presented at the National Bladder Cancer Conference, November 28 to December 1, 1976, Miami Beach, Fla. Supported by Grant CA 18643 from the National Cancer Institute through the National Bladder Cancer Project.

² To whom requests for reprints should be addressed, at Department of Urology, P. O. Box 63635, Memphis, Tenn. 38163.