In vitro carcinogenesis with cells in early passage

Abstract

A well-documented rationale exists for the study of the induction of cancer at the cellular level. Transformation can be quantitated; its frequency follows a linear relationship with dose and is consistent with a "one-hit" phenomenon. Transformed colonies do produce transformed lines with attributes of neoplastic cells including the production of tumors; in vitro activity correlates with in vivo activity to provide evidence that chemically induced carcinogenesis can be studied in vitro. In vitro techniques utilizing mammalian cells in culture have made possible the rapid evaluation of carcinogenicity of agents in man's environment. Neoplastic transformation is inductive and not the result of the selection of preexisting tumor cells. The addition of a host-mediated step in the bioassay makes it possible to decrease the number of false negatives, which may result from the requirement for metabolic activation of the chemical. Thus the in vitro studies described have a high probability of providing practical methods for determining which chemicals in use have a potential of producing cancer. Furthermore, the nature of the cell-target insult interaction can be determined, as well as the chemical nature of the ultimate carcinogen, the degree to which any agent acts alone, be it a chemical, a virus, or irradiation, and the extent to which one agent interacts with another from the same or a different category of carcinogens. Sequential treatment involving chemicals, viruses, and radiation are important, since combinations of various agents may be responsible for an increased risk of cancer in laboratory animals and human populations. The use of multiple agents may also lead to different but specific new types of assays to use for surveillance of our environment for carcinogenic agents. Pretreatment of Syrian golden hamster embryo cells with either X-irradiation or methyl methanesulfonate, but not UV-irradiation, increases the frequency of chemical transformation as does posttreatment with caffeine. Most, if not all, chemical carcinogens will increase the sensitivity of hamster embryo cells to transformation by a carcinogenic simian adenovirus SA7. The enhancement of virus transformation is related to both the length of chemical treatment and the interval between chemical and viral addition. The mechanism of transformation enhancement by various agents has yet to be explained. They may affect a number of molecular processes or cause a modification of existing DNA and thus provide an explanation for carcinogenesis; in fact, in some systems some of these agents may also show mutagenic activity and produce chromosomal aberrations, However, although DNA is the critical site for a mutagen, the critical target(s) of chemical carcinogens is still unknown.