INTRACELLULAR CA2-LYMPHOCYTES IS AFFECTED BY ANTICANCER DRUGS - IMPLICATIONS FOR THE REGULATION OF LEUKEMIC-CELL GROWTH( HOMEOSTASIS IN HUMAN LEUKEMIC T)

The effects of several anticancer drugs on intracellular Ca2+ homeosta sis were analysed in two human leukemic T-cell lines (CCRF-CEM and Jur kat). In CEM cells, significant increases in the free cytosolic Ca2+ c oncentration ([Ca2+](i) were induced by the compounds methotrexate and daunorubicin, whereas adriamycin, vincristine, 6-mercaptopurine and p rednisolone had no effect on [Ca2+](i). In contrast, in Jurkat T-lymph ocytes, methotrexate and also vincristine caused a reduction in the [C a2+](i), as well as a decrease in the [Ca2+](i) changes following cell activation via the T-cell receptor/CD3 complex. In the absence of ext racellular Ca2+, no differences in the Ca2+ levels between drug-treate d and nontreated Jurkat lymphocytes were observed, suggesting that met hotrexate and vincristine were mainly affecting Ca2+ influx across the plasma membrane. Analysis of the effects of methotrexate, daunorubici n and vincristine on the regulation of Ca2+ fluxes across the plasma m embrane were performed in both T-cell lines, by measuring the initial rates of variation of [Ca2+](i) elicited by sudden changes in the extr acellular Ca2+ concentration, [Ca2+](o). In CEM cells, methotrexate an d daunorubicin induced marked decreases In the rate of Ca2+ extrusion, whereas Ca2+ influx was only slightly enhanced upon treatment with th ese anticancer drugs. On the other hand, in Jurkat T-cells, the kineti cs of Ca2+ efflux through the plasma membrane were not affected by pre incubation with the compounds methotrexate and vincristine, although C a2+ influx was significantly inhibited following treatment with these chemotherapeutic agents. Taken together, the observed effects of metho trexate, daunorubicin and vincristine on the mechanisms regulating Ca2 + fluxes across the plasma membrane provide an explanation for the dru g-induced changes in [Ca2+](i) in both leukemic T-cell lines. The pote ntial correlation between these effects on [Ca2+](i) and the growth in hibitory properties of the anticancer drugs will be discussed.