THE EFFECT OF COMBINING ANTITUBULIN AGENTS ON DIFFERENTIATED AND UNDIFFERENTIATED HUMAN COLON-CANCER CELLS

The cytotoxicity of sequential combinations of a taxoid [paclitaxel (T AX) or docetaxel (TXT)] with a vinca alkaloid [vinorelbine (NVB)] was compared in differentiated and undifferentiated HT29-D4 cells. Agents were titrated from low doses inducing no modification of microtubule n etwork to high doses corresponding to the clinically relevant concentr ations that block mitosis. For undifferentiated cells, the sequential combination NVB/TAX was more efficient than TAX/NVB (22% cell survival versus 37% for 5 nM TAX and NVB). Surprisingly, we successively obtai ned synergism for low doses of both compounds [NVB (1-5 nM) and TAX (1 - 15 nM)], then additivity and finally antagonism when one of the comp ounds was at the concentration inducing mitotic block. The three patte rns of results were also obtained with NVB/TXT combinations. For the s ynergistic combinations at the lowest concentrations, cytotoxicity occ urred by apoptosis following mitosis. For differentiated cells, the mo st cytotoxic combinations were 1 mu M TAX or TXT for 3 days followed b y 1 mu M NVB for 3 days, and 0.75 nM TAX or TXT for 9 days followed by 1 mu M NVB for 3 days, the latter producing synergistic effects. Cyto toxicity occurred by apoptosis for the two states of differentiation. Major differences depending on cell phenotype were demonstrated: low s ensitivity of differentiated cells to antitubulin agents and the diffe rence in apoptotic pathways since mitosis is not involved in different iated cells. [(C) 1998 Rapid Science Ltd.].