Add time:07/25/2019         Source:sciencedirect.com

5-Chloro-2′-deoxycytidine (CIdC) + tetrahydrouridine (H4U) sensitizes mammalian cells (HEp-2, RIF-1, 5-180) 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 (CIdU) but display no significant sensitization with CIdC + 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, (a) deoxycytidine kinase → dCMPD, or (b) CD → thymidine kinase, may be sufficient for metabolizing C1dC 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 CIdC + H4U. Both cell lines possess an enzymatic profile consistent with their sensitization to X ray by CIdC + H4U. Dose enhancement ratios of 1.5 to 1.9 for cells treated with CIdC + H4U + 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-deoxycytdine and found these analogs to be X ray sensitizers of mammalian cells. The strategy that we propose with CIdC + 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.

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