Delayed sensitization to heat by inhibitors of polyamine-biosynthetic enzymes.

Exposure of Chinese hamster ovary cells to the enzyme inhibitors methylglyoxal bis(guanylhydrazone and alpha-difluoromethylornithine (DFMO) results in increased sensitivity to hyperthermia. While methylglyoxal bis(guanylhydrazone) demonstrates pronounced cytotoxicity at moderate extracellular concentrations, DFMO is tolerated well by this cell line at concentrations of up to 10 mM, as assayed by clonogenic survival after treatments at 37 degrees. An 8-hr preincubation at 37 degrees with either drug elicits increasing sensitivity to 43 degrees hyperthermia treatments with time after removal of the drug. In contrast to results obtained by heating in the presence of the drugs during the 8-hr exposure, DFMO acts as the more effective sensitizing agent for this delayed effect on progeny of DFMO-treated populations. This phenomenon seems to result from depletion of intracellular putrescine, because the effect can be at least partially recovered by providing the cells with an exogenous source of this diamine. The potential for in vivo heat sensitization by the non-toxic agent DFMO has yet to be investigated but may have intriguing clinical possibilities.