Sensitization to X ray by 5-chloro-2′-deoxycytidine co-administered with tetrahydrouridine in several mammalian cell lines and studies of 2′-chloro derivatives
| Autor: | Sheldon Greer, Liliana M. Perez |
|---|---|
| Rok vydání: | 1986 |
| Předmět: |
Radiation-Sensitizing Agents
Cancer Research Radiosensitizer Cell Survival In Vitro Techniques Deoxycytidine Cell Line chemistry.chemical_compound Tetrahydrouridine medicine Animals Humans Radiology Nuclear Medicine and imaging Uridine Sensitization Radiation business.industry Chinese hamster ovary cell Cytidine deaminase Molecular biology Drug Combinations medicine.anatomical_structure Bromodeoxyuridine Oncology chemistry Deoxycytidylate Deaminase Cell culture Pyrimidine metabolism business |
| Zdroj: | International Journal of Radiation Oncology*Biology*Physics. 12:1523-1527 |
| ISSN: | 0360-3016 |
| DOI: | 10.1016/0360-3016(86)90208-7 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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