Gemcitabine-mediated radiosensitization

Gemcitabine is a potent radiosensitizer of human tumor cells. This review summarizes our preclinical and early clinical studies designed to elucidate the mechanism of action of gemcitabine and phase I trials conducted to determine the optimal dose and schedule. Gemcitabine was found to radiosensitize a wide variety of human tumor cells in culture, particularly cells derived from cancers of the pancreas, breast, and head and neck. Radiosensitization occurs under conditions in which cells demonstrate concurrent redistribution into S phase and deoxyadenosine triphosphate pool depletion. These conditions can be produced by either a long (24-hour) exposure to a low concentration of gemcitabine (10 nmol/L) or by a brief (2-hour) treatment with higher but clinically relevant concentrations (100 nmol/L to 3 micromol/L). Under the latter conditions, sensitization can be detected 4 hours after treatment and last for up to 2 days. These preclinical data were useful in the design of a gemcitabine dose escalation trial in combination with standard radiation for patients with unresectable head and neck cancer. Although this trial is not yet complete, the starting dose of gemcitabine, which is far below the maximum tolerated dose for the drug when used alone, significantly potentiates the toxicity of radiation treatment. We conclude that gemcitabine is a promising radiation sensitizer that needs to be developed cautiously if excessive normal tissue toxicity is to be avoided.