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Synergistic Effect of the v-myc Oncogene with H-ras on Radioresistance¹

Departments of Radiation Oncology [W. G. M., M. C. W., V. J. B.] and Pathology and Laboratory Medicine [M. L. K., R. J. M.], University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and Department of Radiation Oncology, University of California, San Fransisco, School of Medicine , San Francisco, California 94143 [B. E., C. C. L.]

Resistance of tumors to irradiation or chemotherapeutic agents is thought to be one of the reasons why patients who present with early malignancies may not be cured. Much is now known about the molecular mechanisms that underlie drug resistance, but until recently little was known about genetic contributions to radiation resistance. Some evidence now links oncogenes, particularly the ras family of oncogenes, to radiation resistance but heterogeneity between tumors and cell lines has complicated this analysis. Primary rat embryo cells have been chosen as a model system in which the effects on radiation resistance of the ll-ravoncogene could be studied on a uniform genetic background. These cells offer several useful advantages. The cells prior to transformation are diploid. and because they have been in culture only for a few passages prior to transformation with the oncogene it is unlikely that any preexisting mutation affecting radiation response could be present. Additionally, the use of rat embryo cells permitted the study of the effects of a second oncogene on the appearance of the radioresistant phenotype. The results show that the activated li-ras oncogene is associated with radiation resistance in primary rat cells after transformation but that the effect of the oncogene by itself is small. However, the oncogene v-myc, which has no effect on radiation resistance by itself, has a synergistic effect on radiation resistance with H-ras. There appear to be differences in the phenotype of radiation resistance associated with these two forms of transfectants. Thus, radiation resistance seen with H-ras by itself is characterized by a change in the slope of the radiation survival curve at high radiation doses but little or no change within the shoulder region of the radiation survival curve. Radiation resistance seen in H-ras plus v-myc transformants is also characterized by an increase in the slope of the curve at high doses but there is also a large effect within the shoulder region of the radiation survival curve. These studies led to the following conclusions: (a) the radioresistant phenotype is not due to preexisting genetic heterogeneity in the cells prior to transfection; (b) the radiation resistant phenotype of cells transformed by H-ras is seen to a greater degree in cells which also contain the v-myc oncogene; (c) the v-myc oncogene may play an important role in the phenotype of radiation resistance at low doses that is within the range most critical for clinical practice.

¹ This work was supported by grants from the NIH (NCI CA46830) and the W. W. Smith Charitable Trust.

² Supported by a Clinical Oncology Career Development Award from the American Cancer Society and by a Radiological Society of North America Research and Development Fund Scholarship Award.

³ Supported by a Junior Faculty Research Award from the American Cancer Society.

Received 3/ 6/89. Revised 9/26/89. Accepted 10/ 3/89.

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