title: Sensitization to X ray by 5-chloro-2'-deoxycytidine co-administered with tetrahydrouridine in several mammalian cell lines and studies of 2'-chloro derivatives.
abstract: 5-Chloro-2'-deoxycytidine (CldC) + tetrahydrouridine (H4U) sensitizes mammalian cells (HEp-2, RIF-1, S-180) to X ray. This sensitization, as demonstrated previously with HEp-2 cells, is heightened when cells are pre-incubated with inhibitors of pyrimidine synthesis. CHO cells, which intrinsically lack both cytidine deaminase (CD) and deoxycytidylate deaminase (dCMPD), are sensitized to X ray by 5-chlorodeoxyuridine (CldU) but display no significant sensitization with CldC + H4U. The presence and level of these deaminases appears to correlate with X ray sensitization in cell culture. From experiments in cell culture, it can be inferred that one pathway of conversion, deoxycytidine kinase----dCMPD, or CD----thymidine kinase, may be sufficient for metabolizing CldC to a radiosensitizer. However, if both pathways are blocked, as in CHO cells, no X ray sensitization results. In addition to HEp-2 cells, which are extremely elevated in both CD and dCMPD activities, we have examined the sensitization of S-180 and RIF-1 cells to X ray by CldC + H4U. Both cell lines possess an enzymatic profile consistent with their sensitization to X ray by CldC + H4U. Dose enhancement ratios of 1.5 to 1.9 for cells treated with CldC + H4U and ratios of 2.0-2.7 for cells pre-treated with inhibitors of pyrimidine synthesis prior to CldC + H4U have been obtained. Based on reports of the marked X ray sensitization of bacteria by 2'-chloro-2'-deoxythymidine, we obtained 2',5-dichloro-2'-deoxycytidine and 5-bromo-2'-chloro-2-deoxyuridine and found these analogs to be X ray sensitizers of mammalian cells. The strategy that we propose with CldC + H4U and the related 2'-chloro derivatives, based on the elevation of CD and dCMPD in human tumors, offers a degree of selectivity that is not necessarily related to differences in cell kinetics; such that malignancies other than brain tumors may be amenable to this therapy.
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004338:Drug Combinations; D006801:Humans; D066298:In Vitro Techniques; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013767:Tetrahydrouridine / Q000494:pharmacology*; D014529:Uridine / Q000031:analogs & derivatives*
chemical_list: D004338:Drug Combinations; D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D013767:Tetrahydrouridine; C035826:5-chloro-2'-deoxycytidine; C050089:5-bromo-2'-chloro-2'-deoxyuridine; C050090:2',5-dichloro-2'-deoxycytidine; D001973:Bromodeoxyuridine; D014529:Uridine