CELL KILL KINETICS AND CELL-CYCLE EFFECTS OF TAXOL ON HUMAN AND HAMSTER OVARIAN CELL-LINES

Taxol is a clinically active anticancer drug, which exerts its cytotox icity by the unique mechanism of polymerizing tubulin monomers into mi crotubules and stabilizing microtubules. Our studies with ovarian (ham ster CHO and human A2780) cells showed that taxol is a phase-specific agent that is much more cytotoxic to mitotic cells than interphase cel ls. First, the dose-survival pattern of taxol resembled that of other phase-specific agents, in which cell-kill reached a plateau at a certa in concentration. This suggests that the asynchronous cell population consists of a taxol-sensitive (presumably mitotic) fraction and a taxo l-resistant fraction. Second, the cells were more responsive to increa sed exposure time than to increased dose above the plateau concentrati on. Third, in both asynchronous and synchronous cultures taxol was muc h more cytotoxic to mitotic than interphase (G1, S and G2) cells. Four th, the taxol concentration needed to kill cells corresponded to the d ose needed to block cells in mitosis. Although taxol blocked cells in mitosis, the mitotic block was of short duration. Cells escaped the mi totic block, without cytokinesis, and entered the next round of DNA sy nthesis to form multinucleated polyploid cells. Taxol was 15- to 25-fo ld more toxic to A2780 (human ovarian carcinoma) cells compared to CHO cells. This difference in sensitivity correlated with a higher intrac ellular taxol concentration in A2780 as compared to CHO as determined by either an ELISA assay or by [H-3]-taxol uptake.