Cancer chemopreventive agents are typically natural products or their synthetic analogs that inhibit the transformation of normal cells to premalignant cells or the progression of premalignant cells to malignant cells. These agents are believed to function by modulating processes associated with xenobiotic biotransformation, with the protection of cellular elements from oxidative damage, or with the promotion of a more differentiated phenotype in target cells. However, an increasing number of chemopreventive agents (e.g., certain retinoids, nonsteroidal anti-inflammatory drugs, polyphenols, and vanilloids) have been shown to stimulate apoptosis in premalignant and malignant cells in vitro or in vivo. Apoptosis is arguably the most potent defense against cancer because it is the mechanism used by metazoans to eliminate deleterious cells. Many chemopreventive agents appear to target signaling intermediates in apoptosis-inducing pathways. Inherently, the process of carcinogenesis selects against apoptosis to initiate, promote, and perpetuate the malignant phenotype. Thus, targeting apoptosis pathways in premalignant cells--in which these pathways are still relatively intact--may be an effective method of cancer prevention. In this review, we construct a paradigm supporting apoptosis as a novel target for cancer chemoprevention by highlighting recent studies of several chemopreventive agents that engage apoptosis pathways.

REVIEW Apoptosis as a Novel Target for Cancer Chemoprevention

Apoptosis as a novel target for cancer chemoprevention

In a study of the relation between chronic inflammation and carcinogenesis, C3H mouse fibroblasts of the 10T 1/2 clone 8 line (10T 1/2 cells) were exposed to human neutrophils stimulated to synthesize reactive oxygen intermediates or to a cell-free enzymatic system generating superoxide (xanthine oxidase plus hypoxanthine). After exposure, the 10T 1/2 cells were either placed in tissue culture or immediately injected into athymic nude mice. Both malignant and benign tumors developed in the mice injected with treated cells, but not in those injected with control cells; in one instance cells grown from one of the benign tumors subsequently developed a malignant phenotype. Malignant transformation was also observed in treated cells in the experiments in vitro.

https://science.sciencemag.org/content/sci/227/4691/1231.full.pdf

Phagocytes as carcinogens: malignant transformation produced by human neutrophils

This article reviews approximately 700 results reported in the literature with 32 chromium compounds assayed in 130 short-term tests, using different targets and/or genetic end-points. The large majority of the results obtained with Cr(VI) compounds were positive, as a function of Cr(VI) solubility and bioavailability to target cells. On the other hand, Cr(III) compounds, although even more reactive than Cr(VI) with purified nucleic acids, did not induce genotoxic effects in the majority of studies using intact cells. Coupled with the findings of metabolic studies, the large data-base generated in short-term test systems provides useful information for predicting and interpreting the peculiar patterns of Cr(VI) carcinogenicity.

Genotoxicity of chromium compounds. A review.

Metal carcinogenesis: Mechanistic implications

The literature on cell transformation by chemical carcinogens has been critically reviewed. This subject is highly relevant to carcinogenesis in vivo, because the phenotypic changes that are collectively referred to as cell transformation usually involve the acquisition of tumorigenicity on inoculation into suitable rodent hosts. The systems chosen for review fall into 3 categories: cell strains (cells with a limited lifespan); cell lines (cells with an unlimited lifespan); and oncogenic viral-chemical interactions involving cells (Fischer rat embryo cells expressing an endogenous retrovirus, mouse embryo cells expressing the AKR leukemia virus, chemical enhancement of a simian adenovirus, SA7 transformation of Syrian hamster or rat embryo cells). Of the entire literature reviewed, 117 papers have been accepted for data abstraction by pre-defined criteria; these include 41 references to cell strains, 40 in cell lines, and 38 in viral-chemical interactions including cells. Because different systems have been reviewed, it would be meaningless to group all the compounds. The overall summary of the systems is as follows (many compounds have been tested in more than one system and, hence, are duplicated in these totals). (Chart: see text) In general, there is a reasonably good correlation between the results of the cell transformation systems and in vivo carcinogenesis. However, the many deficiencies of the EPA Merged Carcinogen List preclude definitive comparisons. Moreover, a number of 'false negatives' were obtained in systems that did not employ external metabolic activation. Further validation of all systems is required, but it seems very probable that several cell transformation systems will become valuable in assaying (with reasonable time and cost) the carcinogenic potential of environmental chemicals.

Cell transformation by chemical agents--a review and analysis of the literature. A report of the U.S. Environmental Protection Agency Gene-Tox Program.

This study provides a preliminary comparative evaluation of the responses to a series of 49 chemicals, in in vitro transformation assays, of Balb/3T3 cells, Syrian hamster embryo cells, and Fischer 344 rat embryo cells infected with Rauscher murine leukemia virus. The chemicals assayed included aromatic amines; polycyclic aromatic hydrocarbons; alkylating agents; nitrosamines, hydrazines, and related compounds; heterocyclic compounds; amides, ureas, and acylating agents; inorganic compounds; and hormones. In all three assays 37 of the chemicals were tested. The most uniform test responses were obtained with the polycyclic aromatic hydrocarbons and inorganic compounds With the other groups of chemicals, more variation in response was observed. This study expands the base of information on the potential of these in vitro transformation systems, and the lack of responses with some of the chemicals underscores the need for incorporation of exogenous metabolic activating systems into these assay systems.

Comparative Neoplastic Transformation Responses of Balb/3T3 Cells, Syrian Hamster Embryo Cells, and Rauscher Murine Leukemia Virus-Infected Fischer 344 Rat Embryo Cells to Chemical Carcinogens

Roman J. Pienta

Papers

Cell transformation by chemical agents--a review and analysis of the literature. A report of the U.S. Environmental Protection Agency Gene-Tox Program.

Comparative Neoplastic Transformation Responses of Balb/3T3 Cells, Syrian Hamster Embryo Cells, and Rauscher Murine Leukemia Virus-Infected Fischer 344 Rat Embryo Cells to Chemical Carcinogens