Correlates of vincristine resistance in four murine tumor cell lines

The mechanism(s) of cellular resistance to vincristine (VCR) are poorly understood. Four murine tumor cell lines with varying degrees of VCR resistance, as measured by prolonged survival of tumor-bearing mice following VCR treatment, were selected for study. These lines were P1534, P388, P388/VCR and L1210. Steady-state cellular VCR levels, bound intracellular VCR, displaceable intracellular VCR, influx velocities and efflux velocities following VCR preloading were all measured in vitro and correlated with augmentation of survival. Neither the influx velocity, efflux velocity nor the steady-state VCR level showed any apparent correlation with in vivo sensitivity. Moreover, the ratio of influx velocity to efflux velocity was highest in the most sensitive cell line (i.e. P1534) and lowest in the most resistant cell line (i.e. P388/VCR). Bound intracellular VCR correlated best with VCR sensitivity suggesting that high-affinity intracellular binding, presumably to tubulin (Ka congruent to 1 X 10(-7) M), is a critical determinant of VCR sensitivity.