Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5'-Deoxy-5-fluorouridine (5'-DFUR) was parenterally and orally effective on various transplantable tumors and its activity was better than that of other fluorinated pyrimidines. However, like 5-fluorouracil and 2'-deoxy-5-fluorouridine (FUdR), 5'-DFUR was ineffective on L1210 leukemia resistant to 5-fluorouracil, suggesting that it would exert its antitumor activity through converted 5-fluorouracil. In tissue culture, 5'-DFUR inhibited the growth of various tumor cells similarly to ther fluorinated pyrimidines. However, 5'-DFUR was unique in that uridine completely reversed its inhibitory effect. Enzymological study clarified that uridine inhibited the conversion of 5'-DFUR to 5-fluorouracil by a uridine phosphorylase, in parallel to its reverse effect on cell growth inhibition by 5'-DFUR. Furthermore, a subline of L1210 leukemia resistant to 5'-DFUR but not to 5-fluorouracil was found to lack the uridine phosphorylase. These results indicate that 5'-DFUR is a depot form of 5-fluorouracil which can be promptly activated by uridine phosphorylase. In addition, the uridine phosphorylase was found to be abundant in sarcoma-180 solid tumor, leading to a significantly higher concentration of converted 5-fluorouracil in this tumor than in other normal tissues. This provides a good explanation for the high chemotherapeutic index of 5'-DFUR against this tumor, which may be applicable also for other tumors.
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PMID:Role of uridine phosphorylase for antitumor activity of 5'-deoxy-5-fluorouridine. 644 47

A novel phosphoramidate nucleotide prodrug of the anticancer nucleoside analogue 5-fluoro-2'-deoxyuridine (5-FdUrd) was synthesized and evaluated for its cytostatic activity. Whereas 5-FdUrd substantially lost its cytostatic potential in thymidine kinase (TK)-deficient murine leukaemia L1210 and human lymphocyte CEM cell cultures, NUC-3073 markedly kept its antiproliferative activity in TK-deficient tumour cells, and thus is largely independent of intracellular TK activity to exert its cytostatic action. NUC-3073 was found to inhibit thymidylate synthase (TS) in the TK-deficient and wild-type cell lines at drug concentrations that correlated well with its cytostatic activity in these cells. NUC-3073 does not seem to be susceptible to inactivation by catabolic enzymes such as thymidine phosphorylase (TP) and uridine phosphorylase (UP). These findings are in line with our observations that 5-FdUrd, but not NUC-3073, substantially loses its cytostatic potential in the presence of TP-expressing mycoplasmas in the tumour cell cultures. Therefore, we propose NUC-3073 as a novel 5-FdUrd phosphoramidate prodrug that (i) may circumvent potential resistance mechanisms of tumour cells (e.g. decreased TK activity) and (ii) is not degraded by catabolic enzymes such as TP which is often upregulated in tumour cells or expressed in mycoplasma-infected tumour tissue.
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PMID:The cytostatic activity of NUC-3073, a phosphoramidate prodrug of 5-fluoro-2'-deoxyuridine, is independent of activation by thymidine kinase and insensitive to degradation by phosphorolytic enzymes. 2165 73