Nolatrexed dihydrochloride

Chemical Properties

Tan Solid

Uses

Antifolate thymidylate synthase inhibitor. Antineoplastic.

Biological Activity

thymidylate synthase (ts) is a crucial enzyme in the synthesis of 2'-deoxythymidine-5'-monophosphate, an essential precursor for dna biosynthesis. thus, this enzyme is a critical target in cancer chemotherapy. nolatrexed (ag-337) is a non-classical thymidylate synthase inhibitor.

in vitro

nolatrexed was designed using x-ray crystallographic data from the ts molecular modeling and folate binding site. it is a non-classical ts inhibitor in that it lacks a terminal glutamate side chain and is uncharged at physiological ph. nolatrexed does not require a specific transport mechanism to enter into cells and, once within the cell, is not a substrate for the enzyme folyl polyglutamate synthetase [1].

in vivo

when nolatrexed was administered to nude mice bearing bu25tk- tumor xenografts, a time-dependent increase in antitumor activity was observed [1].

IC 50

1.0, 0.81 and 1.0 μm for l1210, ccrf-cem and gc3/m tk- cell lines, respectively

References

[1] hughes an, rafi i, griffin mj, calvert ah, newell dr, calvete ja, johnston a, clendeninn n, boddy av. phase i studies with the nonclassical antifolate nolatrexed dihydrochloride (ag337, thymitaq) administered orally for 5 days. clin cancer res. 1999 jan;5(1):111-8.
[2] rafi i, boddy av, calvete ja, taylor ga, newell dr, bailey np, lind mj, green m, hines j, johnstone a, clendeninn n, calvert ah. preclinical and phase i clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors. j clin oncol. 1998 mar;16(3):1131-41.