[Gemcitabine and ionizing radiations: radiosensitization or radio-chemotherapy combination]

Gemcitabine is a pyrimidine analog which has demonstrated antitumoral activity in a variety of solid tumors including bladder, non-small cell lung and pancreatic cancers. Gemcitabine is a potent radiosensitizer of human tumor cells. This review summarizes preclinical studies designed to elucidate the mechanism of action of gemcitabine with ionizing radiation. Phase I-II ongoing trials of combination of radiation therapy and gemcitabine are trying to determine the optimal dose and schedule which could be used in daily clinical activity. The mechanism of radiosensitization is thought to be simultaneously gemcitabine-induced dATP (deoxyadenosine triphosphate) depletion and cell cycle redistribution into the S phase. Although there are no real study which has proven supra-additive combination, the recent acute side effects in several clinical studies oblige physicists to determine with precision the maximum tolerated dose of gemcitabine in association with ionizing radiation. Radiosensitization conditions can be obtained either with a long exposition to a low concentration or a short exposition to a high concentration. Radiation sensitivity begin to be detected four hours after treatment for 48 hours. A dose about 100 mg/m2/week of gemcitabine could be used with radiation therapy according to recent phase I results. This limiting dose is approaching to a radiosensitization context where the effect of one agent is increased by another agent which is inactive or poorly active for the effect under consideration. In this type of regimen, the two modalities do interact with a frequent inhibition of recovery from potentially lethal damage and a probably increase of late side effects of radiation therapy. In contrast, radio-chemotherapy combination is used for a therapeutic advantage when the drug by itself is active against the tumor but does not enhance late side effects of radiation on the critical normal tissues within the irradiated volume. Gemcitabine surely is a strong radiosensitizer even at low doses with future extended combined modality therapeutic indications. The ultimate goal of combined treatments should be an increased therapeutic ratio.