The induction kinetics of different genotoxic lesions were studied concurrently with the following assays: cytotoxicity, ouabain resistance (oua-r) mutations, morphological neoplastic transformation, DNA damage and repair as measured by alkaline elution, and removal of alkylated DNA adducts as measured by HPLC. The relative levels of response for these biological end points were determined after treatment with the alkylating agents, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-ethylnitrosourea (ENU), for varying exposure periods. The short exposure time (5 min for ENU) required for maximal induction of oua-r mutations and single-strand breaks was found to be similar in BALB/3T3 clone A31-1-1 cells that repair 06-alkylguanine and for CHO cells that are unable to repair this lesion. Maximal transformation of BALB/3T3 cells by ENU required 45-60 min for exposure, and maximal induction of 6-thioguanine-resistant (6-TG-r) mutations in CHO cells also required long exposure times. In CHO cells exposed to ENU, combined treatment with the inhibitors of excision repair 1-beta-dD-arabinofuranosylcytosine (ara-C) and hydroxyurea allowed DNA damage, measured as single strand breaks, to increase for at least 30 minutes of exposure. The induction kinetics of the observed responses appeared to be determined by factors other than the repair kinetics of individual akylated bases. The induction of type IV collagenolytic activity was investigated as a marker of the acquisition of invasiveness, the most advanced malignant phenotype. Marked degradation of labelled type IV collagen substrate was induced by a BALB/3T3 cell line transformed by arsenic. The degradation pattern differed from those reported with other cell types.
