MECHANISMS INVOLVED IN RESISTANCE OF PREIRRADIATED CHINESE-HAMSTER V79 CELLS TO CYTOTOXIC DRUGS ARE MULTIFACTORIAL

We found previously that Chinese hamster V79 cells irradiated with multiple fractions of gamma rays (0.3 Gy of gamma rays daily, five times per week over 12 weeks) become resistant to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and vincristine sulfate (VCR), sensitive to methotrexate and cis-dichlorodiammineplatinum (II), but exhibit no change in their sensitivity to gamma rays and ultraviolet light. The aim of this study was to elucidate the mechanisms by which these cells acquire the resistance to MNNG and VCR. Flow cytometric analysis shows this induced resistance is not the result of parasynchronization, i.e. the selective killing of the cells in the sensitive part of the cell cycle. The levels of protective molecules, glutathione, and metallothioneins were significantly increased in V79 cells irradiated with multiple fractions of gamma rays. Addition of verapamil reverses the resistance of these cells to VCR, suggesting the involvement of plasma membrane-associated P-glycoprotein in acquiring resistance to VCR. We infer that mechanisms of resistance to MNNG and VCR are multifactoral, involving changes in the plasma membrane as well as an increase in the cellular levels of glutathione and metallothioneins. Both mechanisms may be responsible for the non-effectiveness of the treatment for cancer, in which radiotherapy is used during or before chemotherapy.