tetrahydrouridine and Melanoma

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.

Topics: Antineoplastic Agents; Bromodeoxycytidine; Cell Line; Deoxycytidine; Fibroblasts; Humans; In Vitro Techniques; Melanoma; Radiation-Sensitizing Agents; Tetrahydrouridine; Tumor Cells, Cultured; Uridine

Extracts of solid mouse tumors were examined for deoxycytidine kinase and deaminase activities. 1beta-D-Arabinofuranosylcytosine nucleotide was formed at a rate of 45 nmoles/hr by Glioma 26/57 and only 14 nmoles/hr by Ridgway osteogenic sarcoma. Deaminase activity was highest in Lewis lung (114 nmoles of 1-Beta-D-arabinofurano-syluridine formed per hr) and in CaD2 (104 nmoles of u-beta-D-arabinofuranosyluridine formed per hr). Deaminase activity in tumor extracts is sensitive to freezing, while deaminase activity in monkey serum is not. It was observed that kinase activity varies by as much as 50% in different cell lines of the same tumor. In the presence of tetrahydrouridine, kinase activity was significantly increased in most of the tumors studied.

Topics: Adenocarcinoma; Aminohydrolases; Animals; Cell Line; Chick Embryo; Cytarabine; Freezing; Glioma; Lung Neoplasms; Mammary Neoplasms, Experimental; Melanoma; Mice; Mice, Inbred AKR; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Neoplasms, Experimental; Osteosarcoma; Phosphotransferases; Pyrimidine Nucleotides; Sarcoma 180; Tetrahydrouridine; Uridine