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Potentiation of Radiation Effects on Two Murine Tumors by Lonidamine¹

Departments of Radiation Oncology [J. H. K., A. A. A., S. H. K.] and Medicine [C. W. Y.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Lonidamine is a potent inhibitor of spermatogenesis and a hyperthermic sensitizer. The principal established locus of biochemical action of lonidamine is a selective inhibitory effect of the energy metabolism either in NAD-linked reactions in germ cell mitochondria, as well as the glycolytic metabolism of a variety of tumor cell lines by means of inhibition of mitochondrially bound hexokinase. We carried out in vivo tumor experiments to determine whether lonidamine when combined with radiation could potentiate the cytotoxic effects of radiation on two murine tumors. The combined effects of single acute lonidamine (100 mg/kg) and single dose X-irradiation were evaluated on the transplanted methylcholanthrene-induced fibrosarcoma in BALB/c mice and on the radiation-induced fibrosarcoma in C₃H/He mice. The radiosensitizing effect by lonidamine was maximal when lonidamine was administered immediately prior to or after X-irradiation. The dose modifying factor of lonidamine is estimated to be 1.36 for methylcholanthrene-induced fibrosarcoma tumors and 1.25 for radiation-induced fibrosarcoma tumors. There was no disproportionately enhanced skin reaction following the combined treatments. The present results of the potentiating effects of radiation may be attributed, in part, to the findings of cell culture studies that lonidamine is a potent inhibitor of repair of potentially lethal damage.

¹ Supported in part by National Cancer Institute Grants CA-33894 and CA-08748.

² To whom requests for reprints should be addressed.

Received 8/ 7/85. Revised 11/ 8/85. Accepted 11/12/85.

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