2,4-Diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline (TMQ), a potent non-classical folate antagonist inhibitor—I

Bertino, Joseph R.; Sawicki, W. L.; Moroson, Barbara A.; Cashmore, Arlene R.; Elslager, Edward F.

doi:10.1016/0006-2952(79)90655-5

Cited by 76 publications

(20 citation statements)

References 10 publications

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“…We have recently utilized a new inhibitor of DHFR, trimetrexate (TMQ) [39], to treat MTX-resistant cells [33J. Trimetrexate or other folate antagonists that accumulate in cells to high levels and do not use the folate Table 4.…”

Section: H Eradication Of Drug-resistant Cellsmentioning

confidence: 99%

Mechanisms of Drug Resistance in Human Leukemia

Bertino¹,

Srimatkandada²,

Carman³

et al. 1985

Modern Trends in Human Leukemia VI New Results in Clinical and Biological Research Including Pediatric Oncology

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Section: H Eradication Of Drug-resistant Cellsmentioning

confidence: 99%

Mechanisms of Drug Resistance in Human Leukemia

Bertino¹,

Srimatkandada²,

Carman³

et al. 1985

Modern Trends in Human Leukemia VI New Results in Clinical and Biological Research Including Pediatric Oncology

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“…Trimetrexate (TMTX), a 2,4-diaminoquinazoline, is a synthetic inhibitor of dihydrofolate reductase [7, 8]. Like MTX, TMTX increases intracellular concentrations of phosphoribosyl pyrophosphate (PRPP) by inhibiting purine synthesis.…”

Section: Introductionmentioning

confidence: 99%

Sequential Trimetrexate, 5-Fluorouracil and Folinic Acid Are Effective and Well Tolerated in Metastatic Colorectal Carcinoma

Szelényi

Hohenberger²,

Lochs³

et al. 2000

Oncology

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Trimetrexate (TMTX) is a new antifolate which avoids competition for cellular uptake with folinic acid (FA). A regimen of sequential TMTX, FA and 5-fluorouracil (5-FU) has shown efficacy in patients with colorectal cancer. Therefore, we treated 34 previously untreated patients with metastatic colorectal cancer with a weekly chemotherapy regimen consisting of 110 mg/m² of TMTX intravenously, then 24 h later 200 mg/m² of FA (i.v.) and 500 mg/m² of 5-FU (i.v.). Thereafter, 7 doses of oral FA (15 mg) were given at 6-hourly intervals. A treatment cycle consisted of 6 weeks of treatment, then 2 weeks of rest. All patients were treated as outpatients unless complications arose. Thirty-three patients were assessable for tumor response, and all 34 patients were assessable for toxicity. Twelve patients (36%; 95% confidence interval: 25–49%) achieved a partial response. The median duration of response was 8.5 months, and median survival was 14 months. The most common toxicity was diarrhea of grade 3/4, observed in 22% of treatment cycles; this decreased to 8% with early loperamide treatment. Hematologic toxicity was mild. The sequential administration of TMTX, FA and 5-FU is an active regimen in the first-line treatment of metastatic colorectal cancer and warrants further studies.

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“…In contrast to methotrexate, TMQ is a lipid-soluble antifo late which crosses membranes by passive dif fusion. The enhanced membrane permeabil ity of non-polar antifolates such as TMQ may explain their successful application against solid tumors resistant to methotrex ate [1][2][3]. Furthermore, these agents arc ac-structures) which are inhibitors of hepatic mixed function oxidase activity by rat liver microsomes in vitro [20] and in vivo [17.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Metabolism of the ‘Nonclassical’ Antifolate, Trimetrexate (2,4-Diamino-5-methyl-6-[(3,4,5-trimethoxy-anilino)methyl]quinazoline) by Drugs Containing an Imidazole Moiety

Heusner

Franklin

1985

Pharmacology

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2,4-Diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline (TMQ; NSC No. 249008) is a ‘nonclassical’ antifolate which is advocated as an alternative to methotrexate. TMQ is rapidly and extensively demethylated by a cytochrome P-450-mediated oxidation to a weakly cytotoxic compound of increased polarity. In this study, the effects of clinically used imidazole drugs ketoconazole, miconazole, clotrimazole, cimetidine, etintidine, clonidine and cibenzoline on the rat hepatic microsomal demethylation of TMQ in vitro was investigated. The nitrogen-substituted imidazole drugs (ketoconazole, miconazole, and clotrimazole) were potent non-competitive inhibitors of TMQ metabolism with IC₅₀ values obtainable at therapeutic doses (<2 μM). Cimetidine and etintidine were comparatively weak, competitive inhibitors of TMQ metabolism (IC50 > 300 μM) and clonidine and cibenzoline were even less inhibitory (IC50 > 1 mM). The nitrogen-substituted imidazole drugs have the potential to dramatically alter the pharmacokinetic and pharmacodynamic profile of TMQ as well as other drugs in vivo.

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2,4-Diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline (TMQ), a potent non-classical folate antagonist inhibitor—I

Cited by 76 publications

References 10 publications

Mechanisms of Drug Resistance in Human Leukemia

Mechanisms of Drug Resistance in Human Leukemia

Sequential Trimetrexate, 5-Fluorouracil and Folinic Acid Are Effective and Well Tolerated in Metastatic Colorectal Carcinoma

Inhibition of Metabolism of the ‘Nonclassical’ Antifolate, Trimetrexate (2,4-Diamino-5-methyl-6-[(3,4,5-trimethoxy-anilino)methyl]quinazoline) by Drugs Containing an Imidazole Moiety

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2,4-Diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline (TMQ), a potent non-classical folate antagonist inhibitor—I

Cited by 76 publications

References 10 publications

Mechanisms of Drug Resistance in Human Leukemia

Mechanisms of Drug Resistance in Human Leukemia

Sequential Trimetrexate, 5-Fluorouracil and Folinic Acid Are Effective and Well Tolerated in Metastatic Colorectal Carcinoma

Inhibition of Metabolism of the &lsquo;Nonclassical&rsquo; Antifolate, Trimetrexate (2,4-Diamino-5-methyl-6-[(3,4,5-trimethoxy-anilino)methyl]quinazoline) by Drugs Containing an Imidazole Moiety

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Inhibition of Metabolism of the ‘Nonclassical’ Antifolate, Trimetrexate (2,4-Diamino-5-methyl-6-[(3,4,5-trimethoxy-anilino)methyl]quinazoline) by Drugs Containing an Imidazole Moiety