POTENTIAL INTERACTIONS BETWEEN ANTITUBULIN AGENTS AND TEMPERATURE - IMPLICATIONS FOR MODULATION OF MULTIDRUG-RESISTANCE

We analyzed the effect of high temperature (a 1-h incubation at 43 deg rees C) on the accumulation and cytotoxicity of vinblastine and doceta xel in two model cell lines, K562 and MESSA, and their multidrug resis tance (MDR) counterparts, K562/R7 and MESSA/Dx5. High temperature incr eased the amount of intracellular vinblastine and docetaxel significan tly in MESSA cells and, to a much lesser extent, in K562 cells. MDR-po sitive cells retained a profound drug accumulation defect at 43 degree s C, Hyperthermia enhanced the cytotoxic effect of vinblastine (but no t docetaxel) in both K562 and MESSA cells, but not in the MDR-positive variants. PSC833, a potent modulator of P-glycoprotein, induced high levels of drug accumulation in the two MDR-positive cell lines at both 37 degrees C and at 43 degrees C. PSC833 also significantly reduced t he resistance levels of the two MDR-positive lines at both 37 degrees C and at 43 degrees C. The effect of hyperthermia on drug accumulation thus seems to depend on the cell line, whereas the effect on cytotoxi city depends on the type of compound. The MDR phenotype remains a ther apeutic obstacle at 43 degrees C but is accessible to modulation.