Effect on human malignant glioma cell lines and glioma xenografts of anti-neoplastic agents combined with low radiation doses Free

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Malignant gliomas display aggressive local behaviour and are not cured by existing therapies. Human malignant glioma cell lines that are considered radioresistant respond to low radiation doses (<1 Gy) with increased cell killing (low-dose hypersensitivity). We investigated the effects of various anti-neoplastic agents (camptothecin, etoposide, fotemustine, paclitaxel and temozolomide) before and after low radiation doses (< 1 Gy) on several malignant glioma cell lines established in the laboratory. Malignant glioma cells were incubated for 24 hours with each of the anti-cancer agents before or immediately after irradiation. Cytotoxicity was determined with a clonogenic assay. Exposition to anti-cancer agents before irradiation did not alter low-dose hypersensitivity. Exposition to anti-cancer agents after radiation therapy did not alter low-dose hypersensitivity; but a significant enhancement of cytotoxicity was observed. Then, we tested the anti-tumour activity of fotemustine administered alone or in combination with fractionated low radiation doses on a subcutaneous human malignant glioma xenograft in nude mice. The tolerance was excellent in healthy mice with fotemustine alone. However, in grafted animals, the weekly dose of fotemustine administered alone (40mg/kg) or with radiation therapy was not tolerated with the death of all but one animal. Conversely, the daily administration of fotemustine alone (8mg/kg) was safe, and the concurrent administration with low doses of radiation therapy was more effective than the ultrafractionated regimen alone.

Thus, the combination of repeated low-dose irradiations and anti-cancer agents can improve the effectiveness of ultrafractionated radiotherapy on malignant gliomas. The continuous administration of low doses of fotemustine with radiation therapy enhanced the effect of ultrafractionated low radiation doses on cells as well as on tumor xenografts. These results warrant further studies to validate their clinical implications.