MOLECULAR MECHANISMS IN THE ANTIPROLIFERATIVE ACTION OF TAXOL AND TIAZOFURIN

The molecular antiproliferative effects of taxol and tiazofurin were s tudied in human K562 leukemia, and in MCF-7 breast and OVCAR-5 ovarian carcinoma cell cultures. A single treatment with taxol (2 to 100 nM) or tiazofurin (5 to 20 mu M) on K562 leukemia cells resulted in both a differentiation program and apoptosis in the same cell culture. Tiazo furin proved to be the most potent inducer of differentiation among th e inducers, however, taxol had a major impact on induction of the alte rations characteristic of apoptosis. The antiproliferative effect of t iazofurin was mediated by 37 to 85% inhibition of IMP dehydrogenase ac tivity. Both the differentiation and apoptosis induced by tiazofurin w ere dependent on GTP supply. The induction of differentiation and/or a poptosis was mediated by downregulation of c-myc and Ki-ras oncogenes in all three cell lines treated with tiazofurin (by 2 hr) or taxol (by 24 hr). Combined treatments with tiazofurin and taxol exerted a sched ule-dependent, antiproliferative interaction in the cell lines studied . Synergistic inhibition of cell proliferation was observed when cells were pretreated with tiazofurin (10 to 15 mu M) for at least 12 hr, t hen taxol (5 to 15 nM) was added.