Nolatrexed Research Articles

Phase III Randomized Controlled Trial Comparing the Survival of Patients With Unresectable Hepatocellular Carcinoma Treated With Nolatrexed or Doxorubicin

The study objective was to compare the overall survival (OS) of patients with unresectable or metastatic hepatocellular carcinoma (HCC) treated with nolatrexed (NOL) or doxorubicin (DOX). Patients from North America, Europe, and South Africa (N = 445) with HCC were randomly assigned to receive NOL or DOX. Eligible patients had Karnofsky performance status (KPS) > or = 60%, Cancer of the Liver Italian Program (CLIP) score < or = 3, and adequate organ function. Primary end point was OS. Secondary end points included progression-free survival (PFS), objective response rates, and safety. The treatment groups were well-balanced with regards to age, sex, ethnic origin, and underlying liver disease. Randomization was stratified according to KPS and CLIP score. At the time of the final analysis, 377 patients had died. Median OS was 22.3 weeks for NOL and 32.3 weeks for DOX (P = .0068). The hazard ratio was 0.753 in favor of DOX. Objective response rate (complete response [CR] plus partial response [PR]) was 1.4% for NOL and 4.0% for DOX. Median PFS was 12 weeks for NOL and 10 weeks for DOX (P = .7091). Median time to treatment failure was 8.4 weeks for NOL and 9.1 weeks for DOX (P = .0969). Grade 3 and 4 stomatitis, vomiting, diarrhea, and thrombocytopenia were more common in the NOL arm. Alopecia was more common in the DOX arm. More patients were withdrawn from study for toxicity in the NOL arm than in the DOX arm. NOL showed minimal activity in this phase III trial. Further exploration at this dose and schedule in HCC is not warranted.

28 Results of a phase iii randomized controlled study comparing the survival of patients with unresectable hepatocellular carcinoma (HCC) treated with nolatrexed (NOL) or doxorubicin (DOX)

28 Results of a phase iii randomized controlled study comparing the survival of patients with unresectable hepatocellular carcinoma (HCC) treated with nolatrexed (NOL) or doxorubicin (DOX)

Effects of antifolates on the binding of 5-fluoro-2′-deoxyuridine monophosphate to thymidylate synthase

Folate based inhibitors of thymidylate synthase (TS) might facilitate binding of 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP) to TS similar to the natural reduced folate 5,10-methylenetetrahydrofolate (CH 2-H 4-folate). We studied the lipophilic, non-polyglutamatable antifolates Nolatrexed (NTX) and AG331 and antifolates, that can have a polyglutamate side chain like the natural folate CH 2-H 4-folate; GW1843U89, Raltitrexed (RTX) and Multi-targetted antifolate (MTA) and pentaglutamates (RTX-Glu 5 and MTA-Glu 5). The capacity of these compounds to facilitate the binding of [ 3H]FdUMP to Lactobacillus casei TS and an ammoniumsulphate precipitate of human TS was investigated. Only NTX, RTX-Glu 5 and MTA-Glu 5 facilitated FdUMP binding to L. casei TS and their dissociation constant K d (0.2–0.7 μM) was low compared to CH 2-H 4-folate (2.0 μM). The small lipophilic molecule NTX was favorable to the larger AG331. Polyglutamylation, as indicated by the difference in effect of RTX vs. RTX-Glu 5 and MTA vs. MTA-Glu 5, seems to be important for a classical antifolate to facilitate binding of FdUMP to bacterial TS. Effects of antifolates on FdUMP binding to human TS were different. At a low concentration (0.05 μM) NTX, RTX-Glu 5 and MTA-Glu 5 facilitated 3–5 times higher binding of [ 3H]FdUMP to TS than CH 2-H 4-folate. At higher concentrations (0.3–5 μM) of NTX, RTX-Glu 5 and MTA-Glu 5 the FdUMP binding decreased. The complex remained stable in the absence of (anti)folate for at least 24 hr. The K d values of the antifolates for human TS varied from 19 to 387 nM, while the K d of CH 2-H 4-folate for human TS was 351 nM. The Hill coefficients, which indicated the type of cooperativity of the antifolates in the binding of FdUMP to TS were positive (0.58–0.99) at low concentrations (<0.3 μM) and negative (−0.35 to −0.81) at concentrations >0.3 μM except for GW1843U89, which only showed negative cooperativity (−1.70). It was shown with [ 14C]NTX that when the binding of FdUMP decreased at high NTX concentrations, the binding of NTX to TS still increased. This also held for the natural substrate dUMP. The negative cooperativity of the antifolates was clearly concentration dependent. The difference between human and L. casei TS in the FdUMP binding assays with antifolates can possibly be explained by interaction of the two subunits of human TS, which was absent in L. casei TS. The binding of antifolates to one of the two subunits induced a conformational change of the other subunit. This change no longer allowed the binding of FdUMP or dUMP at the active site. In conclusion this study showed that antifolates enhanced the binding of FdUMP to TS, especially at low antifolate concentrations, that are also clinically achievable, e.g. in human plasma.