The mechanism of action of radiosensitization of conventional chemotherapeutic agents

It is not an exaggeration to state that most of the advances in curing cancer in the last decade have come from successful combinations of conventional chemotherapeutic agents with radiation therapy. Further improvements in therapy will depend on understanding the mechanisms by which chemotherapy improves the effectiveness of radiation in model systems and in patients. In this review, we discuss the mechanisms of action of the fluoropyrimidines, gemcitabine, and the platinums. The fluoropyrimidines (5-fluorouracil and fluorodeoxyuridine) increase the effectiveness of radiation chiefly when given before and during radiation. Increased radiation sensitivity occurs in cells that progress inappropriately into S phase in the presence of drug, suggesting a key role for dysregulation of S-phase checkpoints. Gemcitabine may radiosensitize by a similar mechanism, although the relative roles of specific DNA repair pathways (such as homologous end rejoining) and of apoptosis remain to be determined. For both of these categories of drugs, sensitization probably results when cells that are progressing inappropriately through S phase misrepair DNA damage inflicted by radiation. Thus, loss of the S-phase checkpoint in cancer cells may provide the molecular basis for selective killing of tumors compared with normal tissues. Cisplatin has multiple effects on cells, such as adduct formation and DNA damage repair inhibition, but the mechanism for selectivity against cancer cells compared with normal cells is not yet determined. The identification of the enzymatic targets for these drugs offers the potential to develop predictive assays for response and to develop methods of imaging the progress of therapy.