We are analyzing https://link.springer.com/article/10.1007/s00280-003-0625-9.

Title:
Thymidylate synthase inhibitors as anticancer agents: from bench to bedside | Cancer Chemotherapy and Pharmacology
Description:
Thymidylate synthase (TS) is a folate-dependent enzyme that catalyzes the reductive methylation of 2′-deoxyuridine-5′-monophosphate to 2′-deoxythymidine-5′-monophosphate. This pathway provides the sole intracellular de novo source of 2′-deoxythymidine-5′-triphosphate; therefore, TS represents a critical target in cancer chemotherapy. 5-Fluorouracil (5-FU) was synthesized in 1957 and represents the first class of antineoplastic agents to be developed as inhibitors of TS. While 5-FU has been widely used to treat various human malignancies, its overall clinical efficacy is limited. Therefore, significant efforts have focused on the design of novel, more potent inhibitor compounds of TS. These agents fall into two main categories: folate analogs and nucleotide analogs. Five antifolate analogs are currently being evaluated in the clinic: raltitrexed, pemetrexed, nolatrexed, ZD9331, and GS7904L. Our laboratory has identified a novel mechanism of resistance that develops to TS inhibitor compounds, namely drug-mediated acute induction of new TS synthesis; this mechanism is directly controlled at the translational level. The ability of cancer cells to acutely induce the expression of TS may represent a novel mechanism for the development of cellular drug resistance. The future success of TS inhibitor compounds in the clinic may depend on novel strategies to selectively inhibit TS and on novel combination therapies to overcome cellular drug resistance.
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Topics {✒️}

month download article/chapter small-cell lung cancer drug-mediated acute induction 4-dihydro-2-amino-6-methyl-4-oxo-5 o'dwyer pj molecular docking studies anti-cancer drug loaded wild-type p53 synthesis phase i-ii trial article cancer chemotherapy 5-fu-induced p53 expression quinazoline-based inhibitor full article pdf cellular drug resistance intravenous continuous infusion critical target human colon cancer privacy choices/manage cookies tumour response 5-fu-based chemotherapy related subjects human thymidylate synthase thymidylate synthase inhibitors human cell lines thymidylate synthase inhibitor oral folic acid thymidylate synthase gene 5-day continuous infusion thymidylate synthase mrna thymidylate synthase levels squamous cell carcinoma high-dose leucovorin randomized multicenter trial thymidylate synthase protein thymidylate synthase inhibition murine colon tumors tumor cell lines yale cancer center thymidylate synthase expression line therapy dihydrofolate reductase protein meta-analysis human p53 expression p53 mrna form dose-escalation study national cancer institute potent inhibitor compounds prevents translation initiation previously treated patients phase ii trial

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