Survival responses to new cytostatic hexitols of P388 mouse and K562 human leukemia cells in vitro.

The effects of four hexitol compounds [mitolactol, dianhydrogalactitol, 3,4-diacetyldianhydrogalactitol (DiacDAG), and 3,4-disuccinyldianhydrogalactitol]; two vinca alkaloids (vincristine and N-formylleurosine); doxorubicin; and methotrexate on colony formation of P388 and K562 cells were studied and compared. DisuDAG is a new derivative of hexitols with favorable therapeutic indices on rodent tumors. On the basis of IC50 values in molar concentrations, dianhydrogalactitol was five to six times more toxic than DiacDAG, and mitolactol was 36 (K562) or 80 (P388) times more toxic than DisuDAG. N-Formylleurosine was found to be 20 (P388) or 1000 (K562) times less toxic than vincristine. The large difference was due to the high resistance of K562 cells to N-formylleurosine. Both cell lines were very sensitive to doxorubicin: IC50 after 1 hour of exposure of P388 cells = 240 nM and after 1 hour of exposure of K562 cells = 275 nM. Continuous exposure to methotrexate resulted in 11 and 14.5 nM for P388 and K562 cells, respectively. We have not found direct correlation between the length of doubling times and drug sensitivity (doubling time of P388 = 13-14 hours and of K562 = 25 hours). The sensitivity of cell lines was rather tumor-specific and drug-dependent.