Disease relevance of Nolatrexed

• These antiproliferative toxicities of nolatrexed were predictable and reversible [1].
• We report on two randomized trials performed in the USA and Europe, which compared methotrexate and nolatrexed as treatment for patients with recurrent head and neck cancer [2].
• In the nolatrexed arm, the following grade 3-4 toxicities occurred: neutropenia (29.9%) with 3.1% of febrile neutropenia, mucositis (33.3%), and vomiting (10.3%) [2].
• CONCLUSION: This phase II study of nolatrexed in advanced HCC patients, demonstrated minimal activity and significant stomatitis [3].

High impact information on Nolatrexed

• Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors [1].
• Bioavailability was close to 100% and, because inhibition of thymidylate synthase by nolatrexed is rapidly reversible, the slower absorption after a standard meal may result in a shorter duration of noninhibitory concentrations between doses [4].
• Nolatrexed was rapidly absorbed with a median bioavailability of 89% (range 33-116%), with 88% of patients above 70% [4].
• Average trough nolatrexed concentration, but not dose, was significantly related to the % decrease in both thrombocytes (r2 = 0.58; C50 = 6.0 microg/ml, where C50 is the plasma concentration associated with a 50% decrease in thrombocytes) and neutrophils (r2 = 0.63; C50 = 0.6 microg/ml) [4].
• Plasma nolatrexed concentrations and systemic exposure, measured in 14 patients, were dose related, with mean AUC values of 36 mg(-1)ml(-1)min(-1), 50 mg ml(-1)min(-1)and 80 mg ml(-1)min(-1)at the 3 dose levels studied [5].

Biological context of Nolatrexed

• In the clinical study, there was no effect of schedule on the pharmacokinetics of nolatrexed [6].
• Phase II studies of nolatrexed in children at the maximum tolerated dose of 640 mg/m(2)24 h(-1)are warranted [5].
• 2-Amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)-quinazoline dihydrochloride (nolatrexed dihydrochloride, Thymitaq, AG337), a specific inhibitor of thymidylate synthase, was developed using protein structure-based drug design [7].
• In response to nolatrexed alone, HT29 cells were more sensitive than HCT116 cells (GI(50) 1.9 micro M vs 9.8 micro M), with G(1)/S-phase cell cycle arrest occurring within 24 h in both cell lines [8].

Anatomical context of Nolatrexed

• The pharmacokinetic interaction was confirmed by studies with human liver microsomes, nolatrexed being an inhibitor of the major routes of metabolism of paclitaxel [6].
• The simultaneous exposure of HT29 cells to the combination of nolatrexed and cantharidin in drug molar ratios of 1:1 and 1:2.5 for 72 h was synergistic producing composite CIs of 0.88 and 0.87, respectively [8].
• The C18 and C29 cell lines were in general resistant to the other agents tested (methotrexate, 5-fluorouracil, nolatrexed) when compared with the C85 and C86 cell lines [9].

Associations of Nolatrexed with other chemical compounds

• A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq (nolatrexed dihydrochloride) given by 10-day oral administration [7].
• CONCLUSION: Nolatrexed and doxorubicin are minimally active in the treatment of advanced HCC [10].

Gene context of Nolatrexed

• METHODS: RIF-1 and HT29 cells were treated with the TS inhibitors 5-fluorouracil (5-FU) and AG337 (nolatrexed dihydrochloride), as well as cisplatin as control [11].

Analytical, diagnostic and therapeutic context of Nolatrexed

• CONCLUSION: Nolatrexed can be safely administered to patients at a dose of 800 mg/m2/d over 5 days by continuous intravenous infusion and this schedule is associated with antitumor effects [1].
• Nolatrexed plasma concentrations were analyzed by high-performance liquid chromatography [4].

References