Interaction of 2-thio-5-fluoro-dUMP and 4-thio-5-fluoro-dUMP with mammalian normal and tumor and helminthic thymidylate synthases: Influence of c(4)-substituents on specificity for enzyme inactivation Journal Article
| Authors: | Dzik, J. M.; Zieliński, Z.; Cieśla, J.; Bretner, M.; Kulikowski, T.; Shugar, D.; Bertino, J. R.; Rode, W. |
| Article Title: | Interaction of 2-thio-5-fluoro-dUMP and 4-thio-5-fluoro-dUMP with mammalian normal and tumor and helminthic thymidylate synthases: Influence of c(4)-substituents on specificity for enzyme inactivation |
| Abstract: | To determine how 5-fluoro-dUMP modifications may affect its specificity, 2-thio-5-fluoro-dUMP and 4-thio-5-fluoro-dUMP were compared as inhibitors of thymidylate synthases isolated from parental and FdUrd-resistant mouse leukemia L1210 cells, human and rat colon adenocarcinomas, regenerating rat liver and the tapeworm, Hymenolepis diminuta, differing in sensitivity to time- and N5,10-methylenetetrahydrofolate-dependent inactivation by 5-fluoro-dUMP (Ki values ranging from 10-9 to 10-7 M). Inactivation by 2-thio-5-fluoro-dUMP, relative to 5-fluoro-dUMP, was 5-20-fold weaker, with specificity for inactivation of different thymidylate synthases paralleling that of 5-fluoro-dUMP. By contrast, 4-thio-5-fluoro-dUMP showed very different specificity, being as potent an inactivator for some enzymes as 5-fluoro-dUMP, but 45-85-fold weaker for others. The results suggest that an interplay between substituents at C(4) and C(5) of the pyrimidine ring may affect the specificity of thymidylate synthase inactivation. © 1993 Academic Press, Inc. |
| Keywords: | controlled study; unclassified drug; human cell; nonhuman; comparative study; animal cell; mouse; animal; mice; cells, cultured; enzyme activation; dose-response relationship, drug; tumor cells, cultured; liver; leukemia cell; rat; rats; molecular interaction; liver regeneration; thymidylate synthase; carcinoma cell; uridine derivative; thionucleotides; cestode; human; priority journal; article; floxuridine phosphate; fluorodeoxyuridylate; support, non-u.s. gov't; 2 thio 5 fluoro 2' deoxyuridine 5' phosphate; 4 thio 5 fluoro 2' deoxyuridine 5' phosphate; hymenolepis |
| Journal Title: | Biochemical and Biophysical Research Communications |
| Volume: | 195 |
| Issue: | 3 |
| ISSN: | 0006-291X |
| Publisher: | Elsevier Science, Inc. |
| Date Published: | 1993-09-30 |
| Start Page: | 1301 |
| End Page: | 1308 |
| Language: | English |
| DOI: | 10.1006/bbrc.1993.2185 |
| PUBMED: | 8216262 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Source: Scopus |
