Inhibiting ras prenylation increases the radiosensitivity of human tumor cell lines with activating mutations of ras oncogenes

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 gene...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1998-04, Vol.58 (8), p.1754-1761
Main Authors: BERNHARD, E. J, MCKENNA, W. G, HAMILTON, A. D, SEBTI, S. M, YIMIN QIAN, JUNMIN WU, MUSCHEL, R. J
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biological and medical sciences
Blotting, Western
Combined treatments (chemotherapy of immunotherapy associated with an other treatment)
Dose-Response Relationship, Drug
Enzyme Inhibitors - pharmacology
Genes, ras - genetics
Humans
Medical sciences
Methionine - analogs & derivatives
Methionine - pharmacology
Mutation
Pharmacology. Drug treatments
Protein Prenylation - physiology
Proto-Oncogene Proteins p21(ras) - metabolism
Proto-Oncogene Proteins p21(ras) - physiology
Radiation therapy and radiosensitizing agent
Radiation Tolerance - drug effects
Radiation-Sensitizing Agents - pharmacology
Time Factors
Treatment with physical agents
Treatment. General aspects
Tumor Cells, Cultured
Tumors
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Summary: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.
ISSN:0008-5472
1538-7445