The Activation of Carcinogens by Mammary Cells: Inter-Organ and Intra-Organ Specificity

Abstract

Evidence has been presented by epidemiologists that the etiology of the majority of human cancers has environmental factors. It is currently felt that the major environmental factor for cancers other than that of the skin is chemical (1). With the exception of alkylating and acylating agents, almost all chemical carcinogens must be metabolically activated (i.e., converted to an ultimate carcinogen) to initiate neoplasia or induce mutations (1). This activation process is important not only in vivo but is crucial for in vitro systems that are employed to study the mechanisms of carcinogenesis and to screen for environmental chemical carcinogens. Most in vitro models use either various cell homogenate fractions or intact cultured cells to metabolically activate the chemical to be evaluated. For example, Ames and his collaborators (2) use an S9 fraction of liver homogenate to metabolically activate carcinogens; the metabolic derivatives are then assayed for their ability to induce bacterial mutations. Similar systems have been used that employ specific locus mutations in mammalian cells (3,4). In other models, carcinogens are activated by cultured intact mammalian cells. The activity of the metabolized carcinogen is assayed by specific locus mutation or transformation in the activating cell itself (5), or in other co-cultivated cells that have lost their ability to activate carcinogens (6). The validity of using mutagenesis as an endpoint to identify active carcinogens has been reviewed extensively (7).