Pharmacodynamics of mitomycin C in cultured human bladder tumors

The effects of mitomycin C (MMC) concentration and exposure time on the inhibition of tumor cell labeling index (LI) were studied using surgical bladder tumor samples from 14 patients. The bladder tumors were cultured as 1-mm3 fragments on collagen gels. LI was determined by incorporation of [3H]thymidine and autoradiography. All tumors responded to MMC. However, the sensitivity varied significantly between tumors. At a 2-h exposure, the concentrations required for 50 and 90% inhibition (IC50 and IC90) ranged from 0.237 to 14.9 and 2.76 to 74.5 micrograms/ml, respectively. There was an inverse correlation between MMC activity and tumor LI; the IC values were higher for the more rapidly proliferating tumors. Exposure time had a pronounced effect on MMC activity. Shortening the exposure time from 2 to 0.5 h increased the IC50 3-fold, while prolonging the exposure time from 2 to 24 h decreased the IC50 6-fold. To determine the minimum concentration and exposure time necessary to reduce tumor LI by 90%, the data for 6 tumors were computer fitted to the pharmacodynamic relationship Cn x T = k. The analysis showed that, on average, a 2.5-h exposure of 3 micrograms/ml was needed for 50% inhibition and a 7-h exposure of 8 micrograms/ml was needed for 90% inhibition. A comparison of the IC values of MMC determined in this study with the literature values determined using monolayer and spheroid cultures of established human bladder tumor cell lines showed that the drug activity in cultured tumor fragments ranged from 7- to 5300-fold lower than that in established cell lines. In summary, our data demonstrate a heterogeneity in the response of bladder tumors from individual patients to MMC, a decreased sensitivity to MMC with increasing tumor proliferation, and that drug concentration and exposure time are critical determinants of MMC activity.