DNA-REPAIR AND MALIGNANT TRANSFORMATION - EFFECT OF X-IRRADIATION, 12-O-TETRADECANOYL-PHORBOL-13-ACETATE, AND PROTEASE INHIBITORS ON TRANSFORMATION AND SISTER-CHROMATID EXCHANGES IN MOUSE 10T1/2 CELLS

The authors have examined the changes which occur in survival and in the frequencies of chromosomal aberrations, sister-chromatid exchanges (SCE), and malignant transformation during recovery from potentially lethal X-ray damage (PLD) in density-inhibited mouse 10T 1/2 cells. During the first 4 hr of recovery, there was a parallel increase in survival, transformation, and SCE but a decrease in aberrations. With recovery intervals of 4 to 12 hr, there was no further change in survival or aberrations; however, both transformation and SCE declined markedly. Transformation induced by X rays alone or in combination with the tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), was suppressed by exposure to the protease inhibitor antipain. In PLD-recovery experiments, TPA was found to enhance both spontaneous and direct X-ray-induced (no recovery) SCE but to have no effect on recovery-induced SCE. Concomitant exposure to antipain or leupeptin suppressed the TPA and recovery-induced SCE but not the direct X-ray-induced SCE. These results are discussed in terms by two hypotheses: (1) that there may be two biologically important classes of DNA lesions and repair processes induced by X irradiation, one primarily responsible for cell killing and one which leads primarily to mutations and transformations and (2) that mitotic recombination reflected by SCE is an important step in the expression of radiation damage in terms of transformation, as it allows segregation of X-ray-induced recessive mutations in daughter cell populations.