Mitogenesis is only one factor in carcinogenesis

Article Abstract:

A discussion is presented of the importance of mitogenesis (cell division) in carcinogenesis (cancer induction). In the late 1970s, Bruce Ames warned against mutagens (agents that cause mutations) that may be everywhere in the environment, and advocated avoiding synthetic chemicals. In 1990, however, the same author and colleagues have suggested that synthetic chemicals probably pose little cancer risk for people, and that mitogenesis is of far greater significance in carcinogenesis. How important is mitogenesis? Its true significance for malignant change should be evaluated in the context of several pieces of information. One is that malignant cell transformation is a multi-stage process, requiring progressive genetic alteration, cell proliferation (multiplication), and expansion of aberrant cell lines. Recent knowledge has improved researchers' understanding of the relationships between carcinogenesis and several factors (growth factors, cell cycle control mechanisms); interactions among these elements, occurring constantly in the real world, make carcinogenesis extremely complex. If mitogenesis, in itself, were potentially carcinogenic, then normal cell proliferation (such as that during fetal development) should be associated with cancer; clearly, this is not the case. Ames and colleagues have argued that many naturally occurring chemicals are toxic; this may be true, but some synthetic compounds, even in very low doses, cause tumors in mice or rats. Nor are foods that admittedly contain such natural toxins (fruits and vegetables) associated with high cancer rates; the opposite, in fact, is true. The frequency of spontaneous DNA damage, said to be high by Ames, is not predictably associated with mutation; all DNA damage is not equivalent to carcinogenesis. A point in the Ames critique concerned the lack of relevance for humans of standard rodent bioassays. This point is argued. Both Ames and the author of the current article stress the need for additional research concerning carcinogenesis. (Consumer Summary produced by Reliance Medical Information, Inc.)

Mitogens, Ames, Bruce

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Inhibition of serum- and Ras-stimulated DNA synthesis by antibodies to phospholipase C

Article Abstract:

The identification of viral oncogenes, which are responsible for the cancer-causing effects of some viruses, led to the identification of proto-oncogenes, which are similar genes found in all normal cells. Although the proto-oncogenes seem to play a role in the regulation of the cell cycle, the precise biochemical mechanisms remain uncertain. One widely studied proto-oncogene is the ras gene, which, when affected by a mutation, is capable of causing tumors. The oncogenic Ras protein, which is the product of the ras gene, can directly induce physical transformation and DNA synthesis when microinjected into living cells. This microinjection technique provides a method for exploring further the biochemical mechanisms involved. Monoclonal antibodies may be prepared which not only bind to specific proteins, but also inhibit their biological activity. Antibodies to oncogenic Ras, when microinjected along with Ras, inhibit the transformation and DNA synthesis that Ras would otherwise cause. It is also possible to prepare such inactivating antibodies to inositol phospholipid-specific phospholipase C gamma (PLC-gamma). When antibodies to PLC-gamma are microinjected with oncogenic Ras, they inhibit the transformation. However, when antibodies to Ras are microinjected with PLC-gamma, the transformation and DNA synthesis usually seen with PLC-gamma is unaffected. This suggests that the oncogenic Ras protein initiates a series of events which includes the activation of PLC-gamma. Since antibodies to PLC-gamma interrupt this chain of events, the Ras influence is mitigated. However, since the effect of PLC-gamma is "downstream" from Ras, antibodies to Ras cannot influence the effect when PLC-gamma is microinjected. The results indicate that Ras exerts its effect by influencing PLC activity, and the PLC is necessary for the Ras effects. (Consumer Summary produced by Reliance Medical Information, Inc.)

Cocarcinogens

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Tyrosine kinase activity and transformation potency of bcr-abl oncogene products

Article Abstract:

The discovery of viral oncogenes, genes that are responsible for the cancer-causing effects of some viruses, led to the identification of proto-oncogenes, which are similar genes found in all normal cells. Many proto-oncogenes have tyrosine kinase activity, which means that they enzymatically transfer phosphate groups to proteins. This phosphate transfer is believed to be an extremely important mechanism by which cells control and regulate their own function. The c-abl proto-oncogene is affected in some human leukemias, including chronic myelogenous leukemia (CML) and Philadelphia-chromosome-positive acute lymphocytic leukemia (ALL). It has been found that this gene is affected by chromosome rearrangements which lop off part of the abl gene and add on part of the neighboring bcr gene. The protein product of the bcr-abl abnormal gene is found in two forms: a 210,000 dalton molecular weight protein dubbed p210 bcr-abl, normally found in CML, and the smaller 185,000 dalton protein, p185 bcr-abl, found in ALL. Examination of the enzymatic activity of the two altered tyrosine kinases showed that the p185 bcr-abl has higher enzymatic activity. Since this oncogenic protein is consistently associated with a more aggressive type of leukemia, it seems that tyrosine kinase activity might be directly related to the pathogenesis of cancer. (Consumer Summary produced by Reliance Medical Information, Inc.)

Protein tyrosine kinase, Protein-tyrosine kinase, Leukemia, Chromosome abnormalities

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