Nucleoside Radiosensitizers

Abstract

Nucleoside/nucleobase analogs (bromodeoxyuridine, iododeoxyuridine, 5fluorouracil, fluorodeoxyuridine, difluorodeoxycytidine, fluoroadenine arabinoside, fluoromethylenedeoxycytidine) can synergistically enhance ionizing radiation-induced cell killing. These analogs are able to radiosensitize a wide variety of tumor cell types in vitro and several have proven clinical efficacy as well. They share a requirement for intracellular metabolism to phosphorylated forms. As triphosphate analogs they can serve as substrates for nucleic acid synthesis and subsequent incorporation into DNA has been correlated with radiosensitization for bromo- and iododeoxyuridine. Each of these analogs also inhibits an enzyme involved in deoxynucleotide metabolism resulting in depletion of at least one deoxynucleoside triphosphate pool. This effect appears to be responsible for radiosensitization with fluorodeoxyuridine difluorodeoxycytidine and fluoromethylenedeoxycytidine in a manner similar to hydroxyurea which elicits radiosensitization solely through its depletion of deoxynucleotides as a result of ribonucleotide reductase inhibition. In addition these analogs promote accumulation of cells in S-phase which appears to be necessary for radiosensitization. Combined with data demonstrating that mismatch repair defective cells are better radiosensitized by these compounds the evidence suggests that errors in DNA replication contribute to radiosensitization. It is essential to define more completely the mechanism(s) responsible for radiosensitization with these important drugs in order to optimize antitumor efficacy and limit normal tissue toxicity.