Too many rodent carcinogens: mitogenesis increases mutagenesis

Article Abstract:

As scientists' understanding deepens regarding the ways carcinogens exert their effects, many assumptions regarding the use of animals in cancer research must change. Support is presented for the formulation that mitogenesis (induced cell division) increases mutagenesis (the induction of genetic mutations), since dividing cells are at more risk of mutating than cells in the resting phase. Dividing cells have more opportunities to be affected by the very high rate of DNA damage from endogenous (within the cell) mutagens, which is imperfectly repaired. Thus, substances (such as saccharin) that are not toxic to chromosomes may become carcinogens at high doses when they cause mitosis and inflammation. The causes of many human cancers are known to be chronic mitogens, such as hormones in breast cancer or alcohol in liver cancer. In animal studies, the maximum tolerated dose (MTD) of a substance often causes chronic mutagenesis, and it is, therefore, not surprising that about half the chemicals tested at the MTD are carcinogens. The proportions of synthetic and natural chemicals that have been tested and found to be carcinogenic is similar (212 out of 350 versus 37 out of 77, respectively), and a large proportion of the natural pesticides (chemicals produced by plants to protect themselves) that are ingested daily by humans have also been found to be carcinogenic. Even a cup of coffee contains 10 milligrams of rodent carcinogens. The carcinogenic properties of natural substances, however, have not been investigated extensively. Research indicates that a substance that is carcinogenic at the MTD in rodents is not really relevant for evaluating the low-dose risk for people, where mitogenesis does not occur. People routinely ingest a vast array of natural carcinogens. Furthermore, the use of pesticides (of which many people are suspicious) may aid health in other ways, such as by making fruit and vegetables cheaper. Cancer research should focus on controlling the major risks that have been identified, rather than on regulating low levels of synthetic chemicals with no proven role in disease. Animal studies can help in the attempt to uncover the basic mechanisms of carcinogenesis. (Consumer Summary produced by Reliance Medical Information, Inc.)

Research, Complications and side effects, Mitosis, Carcinogenesis, Mitogens, Chemical mutagenesis

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Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene

Article Abstract:

Results from research concerning the genetic basis for colorectal cancer are presented. Tumor cells associated with this kind of cancer, as well as with some lung and bone tumors, may contain an abnormality at a particular position of chromosome 17, the p53 gene. The normal configuration of this locus (the wild-type gene) codes for a protein that suppresses transformation, the process whereby normal cells become malignant. To better understand the role of p53 in DNA replication (the first stages of transformation), experiments were performed to determine whether the protein can function as a transcription factor (the first step in copying DNA). Results showed that p53 was able to activate transcription in the experimental assay used. Interest then turned to the role of p53 mutants in this regard, for which two well-characterized forms were used. Neither could activate transcription. The results support other findings in the medical literature regarding the role of p53 as a tumor suppressor, and indicate that wild-type genes of this sort may lose their ability to suppress tumors when they can no longer activate transcription. Mutations that render the gene powerless as a transcriptional factor may cause it to manufacture a protein with transforming capabilities. (Consumer Summary produced by Reliance Medical Information, Inc.)

Proto-oncogenes, Cell transformation

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