CYTOSTATIC AND APOPTOTIC EFFECTS OF PACLITAXEL IN HUMAN OVARIAN-TUMORS

Purpose. The present study evaluated the cytostatic and apoptotic effe cts of a 24-hr paclitaxel treatment in ovarian tumors. Methods, Three- dimensional histocultures of surgical specimens from patients (n = 17) were used. The cytostatic effect was measured by inhibition of 96-hr cumulative DNA precursor incorporation and induction of apoptosis was determined by morphological changes. Results. Paclitaxel produced part ial inhibition of DNA precursor incorporation in about 40% of tumors ( maximum inhibition of similar to 30%) and induced apoptosis in about 9 0% of tumors (maximum apoptotic index of similar to 15%). In responsiv e tumors, maximum cytostatic and apoptotic effects were achieved at le ss than or equal to 1 mu M With no further enhancement by increasing t he drug concentration to 10 mu M. In individual tumors, the apoptotic effect inversely correlated with cytostatic effect (r(2) = 0.27, p = 0 .031), and the maximal apoptotic index correlated with the LI for the untreated controls (r(2) = 0.38, p < 0.01). More than 95% of apoptotic cells after paclitaxel treatment were labeled with DNA precursor. The incomplete cytostatic and apoptotic effects of paclitaxel and the lin k between DNA synthesis and apoptosis in ovarian tumors are similar to our previous findings in other human solid tumors. Conclusions. These findings suggest that (a) apoptosis is the major paclitaxel effect in advanced ovarian tumors, (b) tumor sensitivity to drug-induced cytost atic effect is opposite to sensitivity to apoptotic effect, (c) paclit axel-induced apoptosis increases with increased cell proliferation and is completed after DNA synthesis, and (d) further increasing the dose to elevate plasma concentration beyond 1 mu M may not improve treatme nt outcome.