The mechanism of action of radiosensitization of conventional chemotherapeutic agents*
Section snippets
5-fluorouracil and fluorodeoxyuridine
5-fluorouracil (5FU) has been used extensively with radiation (for other reviews see1, 2). 5FU has both DNA-directed (through the inhibition of thymidylate synthase) and RNA-directed (through incorporation into the 3 species of RNA) effects. Although the disruption of either RNA or DNA synthesis can produce cytotoxicity, a substantial body of evidence suggests that radiosensitization is a result of inhibition of thymidylate synthase (summarized in1).
There are a number of mechanisms by which 5FU
Gemcitabine
The activity of gemcitabine against a variety of solid tumors combined with evidence that it affected deoxynucleotide triphosphate (dNTP) pools suggested that it might be a radiosensitizer. Initial studies showed significant enhancement of radiation-induced cell killing at both noncytotoxic and cytotoxic concentrations.16 There was no evidence of radiosensitization when the cells were irradiated before gemcitabine exposure, whereas the greatest enhancement ratio was observed when cells were
Platinum analogs
Platinum analogs, and specifically cis-diammino-platinum (II) (cisplatin), cis-diammine-1, 1-cyclobutane dicarboxylatoplatinum(II) (carboplatin), and more recently cis-[(1R,2R)-1,2-cyclohexanediamine-N,N'] [oxalato(2-)-O,O'] platinum (oxaliplatin), are being used clinically in combination with radiation in the treatment of a variety of solid tumors. It is not surprising that the mechanism of the interaction continues to be intensely investigated and is the focus of a number of reports.36, 37, 38
The need for better laboratory-clinical interactions
A fundamental issue in the application of conventional chemotherapeutic agents with radiation concerns determination of the molecular mechanism for the therapeutic index. In the case of the fluoropyrimidines and, perhaps, gemcitabine, it seems likely that dysfunctional S-phase checkpoints in cancer cells may permit inappropriate S phase progression, whereas normal cells arrest at the G1/S boundary and are relatively protected. The selectivity of the platinums radiosensitization remains a
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Address reprint requests to Theodore S. Lawrence, MD, PhD, University of Michigan, Department of Radiation Oncology, 1500 E Medical Center Drive, B2C502 UH, Ann Arbor, MI 48109-0010.