TAXOTERE(R) INHIBITS THE PROLIFERATION AND INDUCES THE DIFFERENTIATION OF HL-60 AND K562 HUMAN MYELOID-LEUKEMIA CELLS IN-VITRO

Abstract

Taxotere(R), a synthetic taxoid, has shown strong antitumor activity in vitro, in animal models and in human ovarian and breast carcinomas and malignant melanoma xenografts. Using clonogenic microassays with agar-containing glass capillaries we confirmed the potent inhibition of Taxotere(R) on the colony formation of murine bone marrow cells (GM-CFC: IC50 = 2.3 x 10(-8) M), human myeloid K562 (IC50 = 4.6 x 10(-9) M), HL-60 leukemia (IC50 = 4.6 x 10(-10) M) and KB human squamous carcinoma cells (IC50 = 2.1 x 10(-9) M). Thus, these tumor cells were 5 to 50 times more sensitive to Taxotere(R) than normal GM-CFU-C. In comparison, Taxotere(R) was found to be 50 to 350 fold more effective on the same tumor cells than cis-platin on the basis of the IC50 values. It is noteworthy that dose-response curves of Taxotere(R) and cis-platin presented different shapes suggesting that Taxotere(R) may have a more favorable therapeutic index. Moreover, Taxotere(R) was also able to induce HL-60 cells to differentiate to monocytes between 10(-10) and 10(-9) M and K562 cells between 10(-9) and 10(-8) M. The differentiation inducing capacity of Taxotere(R) was inversely related to the loss of proliferation potential and occurred at concentrations that did not significantly affect cell viability; hence a direct cytotoxic killing effect may be precluded. Thus, the antiproliferative activity of Taxotere(R) may be attributed not only to its spindle poison like action, but also to its differentiation inducing capacity. These data suggest the need for further studies to evaluate Taxotere(R) in' combination cytotoxic-differentiation therapy.