Selective radiosensitization and cytotoxicity of human melanoma cells using halogenated deoxycytidines and tetrahydrouridine.
The halogenated pyrimidines 5-chloro-2'-deoxycytidine (CldCyd) and 5-bromo-2'-deoxycytidine (BrdCyd) can act as radiosensitizers and cytotoxic agents. It was hypothesized that tumor cells and normal cells might use different metabolic pathways to incorporate these halogenated deoxycytidines into DNA. This difference could potentially be exploited to produce selective radiosensitization and cytotoxicity of human tumor cells compared to normal human fibroblasts. This hypothesis was tested using two human melanoma cell lines and two normal fibroblast cell lines. Either CldCyd or BrdCyd alone caused both cytotoxicity and radiosensitization of tumor and normal cells. The addition of the cytidine deaminase inhibitor tetrahydrouridine (H4U) significantly protected the normal cells but had relatively little effect on the tumor cells. These data indicate that it may be possible to exploit differences between the pyrimidine metabolism of normal cells and melanoma cells to improve the therapeutic index of halogenated pyrimidines both as radiosensitizers and as cytotoxic agents.
Lawrence
T S
TS
Department of Radiation Oncology, University of Michigan, Ann Arbor 48109.
Davis
M A
MA
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001972:Bromodeoxycytidine / Q000494:pharmacology; D002460:Cell Line; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008545:Melanoma / Q000473:pathology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013767:Tetrahydrouridine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014529:Uridine / Q000031:analogs & derivatives*
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D001972:Bromodeoxycytidine; D013767:Tetrahydrouridine; C035826:5-chloro-2'-deoxycytidine; D014529:Uridine