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Tumor Biology

Inhibiting Ras Prenylation Increases the Radiosensitivity of Human Tumor Cell Lines with Activating Mutations of ras Oncogenes

Eric J. Bernhard, W. Gillies McKenna, Andrew D. Hamilton, Said M. Sebti, Yimin Qian, JunMin Wu and Ruth J. Muschel
Eric J. Bernhard
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W. Gillies McKenna
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Andrew D. Hamilton
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Said M. Sebti
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Yimin Qian
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JunMin Wu
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Ruth J. Muschel
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DOI:  Published April 1998
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Abstract

The influence of activated ras oncogenes on the sensitivity of human tumor cells to killing by radiation has been an unresolved question in radiobiology. We have examined this question by measuring the radiation sensitivity of human tumor cell lines with oncogenic mutations in their H- or K-ras genes after treatment with prenyltransferase inhibitors that prevent the posttranslational modification of ras required for its activity. Using two measures of clonogenic survival, we have demonstrated radiosensitization in cell lines with oncogenic H-ras mutations or with oncogenic K-ras mutations when ras processing was inhibited by prenyltransferase inhibitor treatment. In contrast, the inhibition of ras processing in cell lines expressing wild-type ras had no effect on radiation-induced cell death.

The prenyltransferase inhibitors themselves inhibited clonogenic survival in some cases, but this inhibition did not correlate with ras mutational status. Although treatment with prenyltransferase inhibitors and radiation resulted in a greater reduction of clonogenicity than either treatment alone in cells with wild-type ras, treatment with both agents had a synergistic effect on cell killing in tumor cells with ras mutations.

Our results demonstrate that the inhibition of oncogenic ras activity in human tumor cells can reduce the radiation survival of these cells, suggesting that oncogenic ras can contribute to radiation resistance in human tumors. These results further demonstrate the potential of using prenyltransferase inhibitors in combination with radiotherapy in the treatment of human malignancies.

Footnotes

  • ↵1 This work was supported by NIH Grants CA64227 (to W. G. M.) and CA73820 (to E. J. B.).

  • ↵2 To whom requests for reprints should be addressed, at Department of Radiation Oncology, 185 John Morgan Building, University of Pennsylvania, Philadelphia, PA 19104-6072.

  • Received December 15, 1997.
  • Accepted February 18, 1998.
  • ©1998 American Association for Cancer Research.
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April 1998
Volume 58, Issue 8
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Inhibiting Ras Prenylation Increases the Radiosensitivity of Human Tumor Cell Lines with Activating Mutations of ras Oncogenes
Eric J. Bernhard, W. Gillies McKenna, Andrew D. Hamilton, Said M. Sebti, Yimin Qian, JunMin Wu and Ruth J. Muschel
Cancer Res April 15 1998 (58) (8) 1754-1761;

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Inhibiting Ras Prenylation Increases the Radiosensitivity of Human Tumor Cell Lines with Activating Mutations of ras Oncogenes
Eric J. Bernhard, W. Gillies McKenna, Andrew D. Hamilton, Said M. Sebti, Yimin Qian, JunMin Wu and Ruth J. Muschel
Cancer Res April 15 1998 (58) (8) 1754-1761;
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