Chemical oncogenesis in cultured mouse embryo cells in relation to the cell cycle.
Using the C3H/10T 1/2 CL8 line of mouse embryo fibroblasts and three different methods of obtaining cell cycle synchrony, namely arginine or isoleucine deficiency and release from postconfluence inhibition of growth, a sensitive phase for oncogenic transformation induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) has been found. This sensitive phase is located somewhere between the G1/S boundary and a point 4 hr prior to this marker. Methylation of cellular macromolecules by tritiated MNNG is not cycle-dependent in cells synchronized by arginine deficiency. The capacity of cells to repair DNA single strand breaks produced by MNNG was examined by alkaline sucrose sedimentation analysis in cells synchronized by arginine deficiency and treated with MNNG during phases of the cell cycle sensitive and insensitive to oncogenic transformation. Whereas DNA repair was found to be equally rapid in cells treated just before S phase (I), or just after commencement of DNA synthesis (III), transformation was maximal in I. By contrast, cells treated when blocked by arginine deficiency (II) repaired DNA slowly and were not sensitive to malignant transformation. Cells in I and II, which repaired DNA at very different rates, were equally sensitive to MNNG-induced lethality, while cells in III, which repaired DNA at the same rate as cells in I, suffered greater lethality. Thus, in this system it was concluded that there was no direct correlation between DNA repair, as measured by alkaline sucrose sedimentation analysis of prelabeled DNA, and malignant transformation or lethality produced by MNNG. In preliminary experiments malignant transformation induced by cytosine arabinoside (1-beta-D-arabinofuranosylcytosine, ara-C) has been found to occur mainly in S phase, indicating that diverse chemical oncogens may have different sites of action, or that activation of chemical oncogens is cell cycle-specific for some agents.
D000818:Animals; D001120:Arginine / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D003260:Contact Inhibition; D003561:Cytarabine / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts; D007532:Isoleucine / Q000378:metabolism; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D009604:Nitrosoguanidines / Q000494:pharmacology*; D013997:Time Factors
D009604:Nitrosoguanidines; D003561:Cytarabine; D007532:Isoleucine; D008769:Methylnitronitrosoguanidine; D004247:DNA; D001120:Arginine