Disease relevance of Nolatrexed

• Isolation and characterization of thymitaq (AG337) and 5-fluoro-2-deoxyuridylate-resistant mutants of human thymidylate synthase from ethyl methanesulfonate-exposed human sarcoma HT1080 cells [1].
• Radiobiodistribution of intrahepatic arterially injected [125I]IdUrd and Thymitaq was studied in a rat N1S1 hepatoma model [2].
• In vivo studies showed a superior therapeutic effect of combination Thymitaq and [125I]IdUrd in both subcutaneous and ascites tumor models, but the combination of [131I]IdUrd and [125I]IdUrd may be more effective than Auger electron emitters alone for the treatment of subcutaneous tumor [2].
• The potentiation of radiation response in human colon carcinoma cells in vitro and murine lymphoma in vivo by AG337 (Thymitaq), a novel thymidylate synthase inhibitor [3].
• The relationship between intrinsic thymidylate synthase expression and sensitivity to THYMITAQ in human leukaemia and colorectal carcinoma cell lines [4].

High impact information on Nolatrexed

• We postulate that the D49G or G52S mutation leads to the structural perturbation of the highly conserved Arg50 loop, decreasing the binding of thymidylate synthase to the inhibitors, Thymitaq and fluorodeoxyuridylate [1].
• The I108A mutant confers resistance to raltitrexed and Thymitaq with respective IC50 values 54- and 80-fold greater than wild-type but less resistance to BW1843U89 (6-fold) [5].
• Thymitaq-resistant clonal derived sublines were established, and analysis indicated that both gene amplification and point mutations contributed to drug resistance [1].
• High-titer retroviral packaging cells were generated with OPTecTS and >80% of transduced mouse hematopoietic progenitor cells are resistant to raltitrexed, Thymitaq, and U89 at concentrations that eliminated colony growth of mock-transduced cells [6].
• METHODS: The synergistic effect of combination [125I]IdUrd and Thymitaq in clonogenic survival and DNA incorporation was shown on the human hepatoma cell line Hep3B [2].

Chemical compound and disease context of Nolatrexed

• Synergy between the non-classical thymidylate synthase inhibitor AG337 (Thymitaq) and cisplatin in human colon and ovarian cancer cells [7].
• METHODS: Five patients with advanced gastrointestinal cancer were PET scanned both before and 1 hour after oral administration of the TS inhibitor AG337 (THYMITAQ [nolatrexed]); seven control patients were scanned twice but not treated with AG337 [8].

Biological context of Nolatrexed

• Phase I studies of p.o. administered nolatrexed dihydrochloride (AG337, THYMITAQ), a nonclassical thymidylate synthase inhibitor, were performed to establish the maximum tolerated dose and a recommended dose for Phase II studies [9].
• AG337 (Thymitaq) is an antitumor compound synthesized by Agouron Pharmaceuticals, Inc., using protein structure-based drug design [10].
• Initial clinical trial and pharmacokinetics of Thymitaq (AG337) by 10-day continuous infusion in patients with advanced solid tumors [11].
• In L1210 cells zVAD.fmk inhibited DNA fragmentation induced by Thymitaq but did not influence other cell cycle events (S-phase arrest) or the biphasic mitochondrial alterations, indicating caspase involvement downstream but not upstream of the mitochondria following TS inhibition [12].

Anatomical context of Nolatrexed

• In HL60 cells, zVAD.fmk reduced the hyperpolarization of delta psi m observed with Thymitaq alone and failed to inhibit the increase in the sub-G1 population induced by Thymitaq [12].

Associations of Nolatrexed with other chemical compounds

• The F225W mutant displays resistance to BW1843U89 (17-fold increase in IC50 values), but no resistance to raltitrexed and Thymitaq [5].
• WiDr-4PEM and WiDr-cPEM showed cross-resistance to the polyglutamatable TS inhibitor Raltitrexed (6- and 19-fold, respectively) and the nonpolyglutamatable TS-inhibitor Thymitaq (6- and 42-fold, respectively) but not to 5-fluorouracil [13].
• Ab initio studies of some amino acid residue complexes with 4-mercaptopyridine as a model for thymitaq (AG337), an inhibitor of thymidylate synthase [14].

Gene context of Nolatrexed

• Eight mutant cDNAs that were identified from Thymitaq-resistant sublines were generated by site-directed mutagenesis and transfected into thymidylate synthase-negative cells [1].
• We report improved incorporation of the radiolabeled-thymidine analog [125I/131I]5-iodo-2'-deoxyuridine ([125I/131I]IdUrd) into DNA by the addition of Thymitaq, a thymidylate synthase inhibitor, as a strategy of molecular radiotherapy for hepatoma treatment [2].
• For the leukaemic cell lines, only a twofold range in sensitivity to THYMITAQ was observed (IC50 0.87-2.3 microM), and this did not correlate with TS activity, TS protein or TS mRNA levels [4].

Analytical, diagnostic and therapeutic context of Nolatrexed

• Thymitaq in plasma was assayed by a validated isocratic reverse-phase HPLC assay with detection at 273 nm [11].

References