Possible etiologic mechanisms in chemical carcinogenesis.

Abstract

Some highlights in the development of our knowledge about carcinogens as etiological agents for cancer are reviewed briefly. Advances during the past 20 years relating to metabolic activation with the genesis of reactive metabolites, molecular targets and their interactions with activated carcinogens, oncogenes as molecular targets and the dependence on cell proliferation, all relating to the initiation process, are reviewed. Critical to initiation is the new phenotype in the initiated cell, known only in one instance, the rat liver, in which the characteristic change is one of resistance to many xenobiotic influences. The need for clonal expansion of initiated cells as essential for carcinogenic effects is discussed. Differential inhibition has been shown as a dominant mechanistic pattern in the liver. In other systems, the manner in which clonal expansion is achieved is not evident. The need for studies of the processes involved in carcinogenesis, as well as the agents, is emphasized, in view of the continuing validity of the cell concept as the key to integrating the increasingly large volume of data from the molecular with the biological.

ICRP Publication 131: Stem Cell Biology with Respect to Carcinogenesis Aspects of Radiological Protection

“…The preneoplastic phenotype in vivo is usually initially recognised as a focus of autonomously proliferating cells that often exhibit surface antigen or cytosolic enzymatic alterations. The subsequent appearance of neoplasia at the sites of such lesions has been well documented in experimental models in a variety of tissues (Farber, 1987), but it is not clear which factors dictate the eventual development of clinical cancer. The relatively restricted window of carcinogen susceptibility that is evident during or around puberty in both rodents and humans has been postulated to either contain the greatest number of target cells or be a critical period of stem cell regulation (Boice, 2001).…”

Mutagenesis and carcinogenesis: Endogenous and exogenous factors

“…The study of mechanisms of carcinogenesis is a rapidly developing field and is essential for understanding both the role of mutagenicity tests and methods for rational risk assessment in regulatory policy. Both DNA damage and cell proliferation (i.e., promotion) are essential aspects of carcinogenesis, and agents that increase either are carcinogens Farber, 1987;Pitot et al, 19871. The classical chemical promoters such as phenobarbital and tetradecanoyl phorbol acetate would be expected to be, and are in fact, carcinogens in animals when tested thoroughly [Iversen, 19881. In nondividing tissues, such as the liver (a major target site for carcinogens in rodents [Gold et al, 1989a]), mutation is not sufficient for carcinogenesis: Cells are communicating and telling each other not to grow [Trosko, 1988;Trosko and Chang, 1988;Yamasaki et al, 19881.…”

“…It is important to evaluate risks of synthetic chemicals against the background of the chemicals we encounter from agents causing cell proliferation exhibit thresholds [Farber, 1987;Pitot et al, 19871. Carcinogenesis is a multihit and multistage process. Several mutations appear necessary for carcinogenesis; there are many layers of defense against carcinogens, and most of these defenses are inducible.…”

“…Administering chemicals in cancer tests at the maximum tolerated dose (MTD) commonly causes cell proliferation and inflammatory reactions Farber, 1987;Pitot et al, 1987;Swenberg et al, 19871. It seems likely, therefore, that a high percentage of all chemicals, both man-made and natural, will cause cell proliferation at the MTD and be classified as carcinogens.…”

“…Mutagens, because they damage DNA, are very effective at killing cells and thus are very effective at causing cell proliferation and inflammatory reactions. If a chemical is nonmutagenic and its carcinogenicity is due to cell proliferation resulting from near-toxic doses, one might commonly expect a threshold Farber, 1987;Pitot et al, 19871. natural sources to have our priorities related to risk. Nature's pesticides are the major "toxic chemicals" ingested by man.…”