Aerobic Radiosensitization by SR 4233 in Rodent and Human Cells: Mechanistic and Therapeutic Implications

Summary

Mammalian cells surviving exposure to the bioreductive, cytotoxic agent SR 4233 under hypoxic conditions are sensitized to X-irradiation under aerobic conditions (and in the absence of drug). Fits of both the single-hit, multi-target and linear-quadratic expressions to survival data, as well as direct measurement of surviving fractions after a dose of 2 Gy, indicate that the aerobic radiosensitization produced by SR 4233 can increase both the initial and final ‘slopes’ of the X-ray survival curve. The amount of radiosensitization produced, and whether the modification is principally in the slope or shoulder region of the survival curve, varies from cell line to cell line. Rodent cells are radiosensitized equally whether the drug treatment is given immediately before or after, the irradiation, but human cells are only sensitized for SR 4233 exposure administered before irradiation. Using rodent CHO cells, time-course experiments for SR 4233 and X-rays given in sequence, in which an interval of up to 2h was interposed between the treatments, reveal different kinetics for the loss of radiosensitization depending on whether the hypoxic drug exposure was given before or after the aerobic irradiation. When SR4233 treatment is given pre-irradiation, the radiosensitization effect persists for at least 2h, but it does not when drug is given after irradiation. Taken together, the finding of a difference between rodent and human cells with respect to post-irradiation sensitization by SR4233, and the differing time-course kinetics for this effect as a function of how the drug and radiation are sequenced, suggest that while SR4233 behaves in a radiomimetic manner in most respects, there may be subtle differences in the nature of the lesions produced by the drug, the important cellular targets for this damage, and/or the cell's management of the damage.