Cancer oncogenicity studies

Wenzel-Hartung RP, Brune H, Klimisch HJ Dermal oncogenicity study of 2-ethylhexyl acrylate by epicutaneous application in male C3H/HeJ mice. J Cancer Res Clin Oncol 115 543-549, 1989... 

In mice, three initial oncogenicity studies performed by Innes ef at. (1969) and the L"S National Cancer Institute (1979), where diets containing up to 3(H), 1112 and 2804 ppm, respectively, of PBO were fed for a minimum of 69 weeks, revealed no statistically significant difference in uttnour incidence between treated and control ani mills. However, a fourth, more recent, study performed by... 

Generation of new data leads to new conclusions and interpretations. An oncogenicity study may provide a negative indication of cancer potential and thus validate present exposure controls. On the other hand, a positive indication of carcinogenic potential may trigger both a reevaluation of exposure controls and the need for further data generation. 

Eadier reports of a link between testicular cancer and DMF exposure have not been corroborated ia a study of 4000 Du Pont employees (34). Very recendy, inhalation studies ia mice and rats have shown no oncogenic effect from DMF (35). The International Agency for Research on Cancer (lARC) has concluded that evidence associating DMF with cancer ia animals is "iaadequate," but has classified DMF as "possibly carciaogenic to humans" (Group 2B) (36). 

Many human diseases are caused when certain proteins are either over- or underexpressed. Eor example, breast cancer can be induced by overexpressing certain cellular oncogenes within mammary tissue. To study the disease, researchers produce a line of transgenic mice that synthesize an abnormal amount of the same protein. This leads to symptoms of the disease in mice that are similar to what is found in humans. A protein can be overexpressed by inserting a DNA constmct with a strong promotor. Conversely, underexpression of a protein can be achieved by inserting a DNA constmct that makes antisense RNA. This latter blocks protein synthesis because the antisense RNA binds and inactivates the sense mRNA that codes for the protein. Once a line of mice is developed, treatments are studied in mice before these therapies are appHed to humans. 

Toxicity and effectivity studies have often been performed in rodent fibroblast cells containing oncogenic H-Ras. However, prenylation of K-Ras B and N-Ras are not as effectively blocked by the farnesyltransferase inhibitors as H-Ras [48] (see below). Thus normal cells may be less sensitive to these drugs because they express K-Ras 4B and N-Ras. In this context it should be noted that H-Ras mutations are relatively uncommon in human tumors [49]. Rather, the K-Ras gene is the most frequently mutated in solid human cancers, whereas N-Ras is prevalent in leukemias. Thus the preclinical evaluation of the farnesylation inhibitors has yet to be critically re-evaluated for trials in humans. 

Although the study of inherited cancer syndromes has led to the identification of a number of tumor suppressor genes and oncogenes, the inherited cancer syndromes are thought to account for only about 1% of all cancers. However, somatic (as opposed to germline) mutations in many of these tumor suppressors and proto-oncogenes play a key role in the causation of noninher-... 

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