Cell killing, kinetics, and recovery responses induced by 1,2:5,6-dianhydrogalactitol in dividing and nondividiing cells in vitro.

The survival and cell kinetics effect of 1,2:5,6-dianhydrogalactitol, NSC-132313 (galactitol), were studied on mammalian cells. Nondividing or plateau-phase cells were almost two times more sensitive to galactitol than were cells treated in the dividing state (dose required to reduce survival by 63% on the exponential part of the survival curve (DO)=4.2 mug/ml/hr for dividing cells vs. DO=2.4 mug/ml/hr in nondividing cells). The survival curves were characterized as having shoulder regions, followed by exponential decreases in survival as the drug doses were increased above 12 mug/ml for 1 hour. Synchronized mitotic and G1 phase cells were equally sensitive to galacitol, with approximately 90% of the cells killed by 1-hour exposures to 12.5 mug galactitol/ml. Cells in early S phase were the least sensitive to this drug dose (survival greater than 20%); however, the cells became more sensitive as they progressed through the S phase and into the G2 phase. There were no large differences observed in survival sensitivities anywhere in the cell cycle, suggesting that galactitol was not a cell-cycle phase-specific agent. Cells in mitosis or G1 phases of the cell cycle at the time of treatment with galacitol progressed normally into the next stage of the cell cycle; however, cells exposed to galactitol in S or G2 phases exhibited dose-dependent delays in those phases of the cell cycle. Nondividing cells exposed to high doses of galactitol could not recover from potentially lethal damage (PLD); however, nondividing cells exposed to lower galactitol doses (lethal dose to 10% of the cells) did exhibit slight recovery from PLD. Dividing cells did not recover from PLD at any of the doses tested. Both dividing and nondividing cells were more sensitive (cell kill) to galactitol when it was administered in two dose fractions 4-8 hours apart than when the same total integral dose was given as a single exposure. A 25-50% greater cell kill was achieved in nondividing cell populations given two dose fractions versus a single exposure to galactitol. Up to 60% greater cell kill was obtained with fractionalated doses in dividing cell populations. These responses to fractionated dose treatments were also dose-dependent.