Genetic and molecular mechanisms of the in vitro transformation of Syrian hamster embryo cells by the carcinogen N-ethyl-N-nitrosourea. I. Correlation of morphological transformation and enhanced fibrinolytic activity to gene mutation, chromosomal alterations and lethality

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Abstract
The role of chromosomal alterations, as opposed to gene mutations, in the origin of early stages of the in vitro transformation of Syrian hamster embyro (SHE) cells was investigated. For that purpose we compared the rates at which SHE cells recover from potential tumorigenic, mutagenic, clastogenic and cytotoxic damage if they are held in confluence in low serum medium for 3 or 6 days following a single treatment of N-ethyl-N-nitrosurea (ENU) before the cells are allowed to divide and to express this damage. The results show: (i) that frequencies of gene mutations remain constant; (ii) frequencies of sister chromatid exchange (SCE) and cytotoxicity decrease with very similar kinetics; and (iii) frequencies of chromatid aberrations and micronuclei decrease rapidly in the first 3 days, but slowly or not at all between days 3 and 6. Thus, all the mutational damage and a small fraction of the clastogenic damage still persist after 6 days confluent holding. From the two early stages of in vitro transformation studied, morphological transformation and enhanced fibrinolytic activity, the former shows similar kinetic behaviour as chromatid aberrations and micronuclei, whereas the kinetics of the latter correspond with those of gene mutations. Neither is correlated to SCE or cytotoxicity. Our results suggest that chromosomal alterations can play a major role in induction of morphological transformation of SHE cells. Insofar as enhanced fibrinolytic activity is due to a genetic change, gene mutations can be reponsible. Our observations further indicate that different types of ENU-induced DNA lesions are involved in gene mutations, SCE and cytotoxicity, and clastogenic damage. We have reported the results of experiments analysing these relationships in another paper.

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