Pharmacodynamics of doxorubicin in human prostate tumors

The pharmacodynamics of doxorubicin in human prostate tumors were studied using histocultures of radical prostatectomy specimens. Drug treatment lasted 96 h. The antiproliferative effect was measured by the inhibition of DNA precursor ([3H]thymidine) incorporation, and the cytotoxic effect was measured by monitoring cells with fragmented DNA, as indicated by the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay. The average [3H]thymidine labeling index in 17 tumors was 39% (range, 20-56%). The antiproliferative and cytotoxic effects were concentration dependent and reached 100% at 6 and 17 microM doxorubicin. The cytotoxic concentrations were significantly higher than the antiproliferative concentrations, indicating that prostate tumors were more sensitive to the antiproliferative effect than they were to the cytotoxic effect of doxorubicin. The antiproliferative effect was inversely correlated with patient's age (P < 0.02) and weakly correlated with LI and Gleason grade (P = 0.07 and 0.06, respectively), but it was not correlated with clinical stage, prostate-specific antigen secretion, or race of patients (P > 0.12). In contrast, the cytotoxic effect was positively correlated with Gleason grade (P < 0.05) and weakly correlated with stage (P < 0.08), but it was not correlated with the other parameters (P > 0.18). The opposite correlations between the two effects with tumor grade suggest that the two effects are not coupled. A comparison of the drug concentrations required to produce 50% antiproliferative (0.06 microM) and cytotoxic (2 microM) effects and the literature data on plasma drug concentrations derived from systemic treatment suggest that there are minimal drug effects at the clinically achievable drug concentrations and that regional delivery of doxorubicin to the prostate may be necessary to provide adequate concentrations to produce antiproliferative and cytotoxic effects.