Differential time dependency of antiproliferative and apoptotic effects of taxol in human prostate tumors.

The pharmacodynamics of taxol in human prostate tumors were studied using histocultures of radical prostatectomy specimens from 34 patients. The results showed that taxol inhibited DNA synthesis and induced apoptosis in all tumors. The taxol-induced DNA inhibition and the apoptotic index increased with drug concentration, but reached a maximal plateau level at a concentration between 120 and 1,200 nM. Increasing the concentration by 10- to 100-fold to 12,000 nM did not significantly increase either effect. To address the existing controversy regarding the effect of treatment duration on cytotoxicity, we evaluated two treatment schedules, (i.e., 24 and 96 hours). Prolonging the treatment time from 24 to 96 hours significantly increased the average maximal inhibition of DNA synthesis (E(max)) from 47% to 70% (p < 0.001) and reduced the incidence of relatively resistant tumors (E(max) < 30%) from 31% to 0% (p = 0.04). By contrast, the prolonged treatment time did not increase the apoptotic effect (p = 0.48). The inter-tumor variation in sensitivity to the antiproliferative effect was substantial; the drug concentration required to produce a 30% DNA inhibition (IC(30)) showed a >300,000- and a 14,000-fold range for the 24 and 96 hour treatments, respectively. In conclusion, data of the present study demonstrate (1) antiproliferative and apoptotic effects of taxol in human prostate tumors, (2) that neither effect was significantly enhanced by increasing the drug concentration above 1,200 nM, and (3) that the antiproliferative effect was affected more significantly by drug exposure time than the apoptotic effect.