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Influence of Heat on the Intracellular Uptake and Radiosensitization of 2-Nitroimidazole Hypoxic Cell Sensitizers in Vitro¹

Department of Radiology, Stanford University School of Medicine, Stanford, California 94305 [D. M. B., M. S. C., R. G-M., G. M. H., J. M. B.], and Department of Radiology, State University of New York, Upstate Medical Center, Syracuse, New York 13210 [R. H. S.]

The effect of elevated temperature (44°) on the intracellular uptake of the 2-nitroimidazole hypoxic cell radiosensitizer, misonidazole (MIS), and analogues more hydrophilic than MIS was studied in Chinese hamster ovary cells. It was found that the intracellular uptake of these compounds which enter cells by restricted passive diffusion can be enhanced approximately 4-fold when incubated at 44° compared to the uptake at 37°. Peak intracellular uptake (expressed as the ratio of intracellular concentration to extracellular concentration) following incubation of cells in 2 mM MIS was 100% at 44° but only 25% at 37°. Furthermore, a short-term nonlethal heat pulse (44° for 15 min) with MIS present caused a 2-fold enhancement in uptake which was sustained for an additional 45 min at 37°. This same nonlethal heat pulse was found to induce a similar enhancement in uptake even when MIS was added at subsequent time intervals at 37°. The heat pulse induced a time-related enhancement of uptake at 37° which increased for 1 hr and persisted for at least 6 hr. Finally, in vitro radiosensitization studies of hypoxic Chinese hamster ovary cells showed that the nonlethal heat pulse of 44° for 15 min could greatly enhance the sensitization by low concentrations (0.5 mM) of MIS added after heating due to increased intracellular concentrations of the drug. MIS (0.5 mM) alone achieved a radiosensitization enhancement ratio of 1.29 (compared to irradiated hypoxic cells alone), while the addition of the short-term heat pulse, which had only a minor effect itself, achieved an enhancement ratio of 1.78.

¹ Supported by NIH Grants CA 15201 and CA 04542.

² To whom requests for reprints should be addressed, at Department of Radiology, Division of Radiobiology Research, Stanford Medical Center, Stanford, Calif. 94305.

Received 10/ 8/82. Accepted 4/ 1/83.