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Potentiation of radiation effects on two murine tumors by lonidamine
Abstract:
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.
Insights
Lonidamine enhances radiation therapy effectiveness against murine tumors by inhibiting DNA repair. This drug, a potent inhibitor of spermatogenesis, shows promise in potentiating cytotoxic effects of X-irradiation.
Area of Science:
- Oncology
- Radiation Oncology
- Cancer Biology
Background:
- Lonidamine is a known inhibitor of spermatogenesis and a hyperthermic sensitizer.
- Its biochemical action involves inhibiting energy metabolism in germ cell mitochondria and tumor cell glycolysis via hexokinase inhibition.
Purpose of the Study:
- To investigate the potential of lonidamine to enhance the cytotoxic effects of radiation therapy in vivo.
- To evaluate the combined effects of lonidamine and X-irradiation on two specific murine tumor models.
Main Methods:
- In vivo tumor experiments were conducted using methylcholanthrene-induced fibrosarcoma in BALB/c mice and radiation-induced fibrosarcoma in C3H/He mice.
- Lonidamine (100 mg/kg) was administered acutely, immediately before or after a single dose of X-irradiation.
Main Results:
- Lonidamine demonstrated a radiosensitizing effect, with maximal efficacy when administered around the time of X-irradiation.
- The dose modifying factor for lonidamine was estimated at 1.36 for methylcholanthrene-induced fibrosarcoma and 1.25 for radiation-induced fibrosarcoma.
- No disproportionately enhanced skin reactions were observed in the combined treatment groups.
Conclusions:
- Lonidamine potentiates the cytotoxic effects of radiation therapy on murine tumors.
- This potentiation may be partly due to lonidamine's inhibition of potentially lethal damage repair, as suggested by cell culture studies.