Quinazoline antifolates with dual biochemical loci of action. Biochemical and biological studies directed towards overcoming methotrexate resistance

• Published in: European journal of cancer Vol. 16; no. 5; pp. 713 - 722
• Main Authors: Calvert, A.H., Jones, T.R., Dady, P.J., Grzelakowska-Sztabert, B., Paine, R.M., Taylor, G.A., Harrap, K.R.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.1980
• Subjects: Animals; Cell Survival - drug effects; Female; Folic Acid - metabolism; Folic Acid Antagonists; Leukemia L1210; Methotrexate - metabolism; Methotrexate - pharmacology; Mice; Quinazolines - pharmacology; Quinazolines - toxicity; Thymidylate Synthase - antagonists & inhibitors
• ISSN: 0014-2964
• DOI: 10.1016/0014-2964(80)90214-5

We report experiments on two substituted quinazolines, which are inhibitors both of dihydrofolate reductase and thymidylate synthetase, N-(p-(((2,4-diamino-5-methyl-6-quinazolinyl)methyl)amino)benzoyl)- l-glutamic acid (CB 3703) and N-(p-(((2-amino-4-hydroxy-6-quinazolinyl)methyl)amino)benzoyl)- l-glutamic acid (CB 3705). CB 3703 inhibits dihydrofolate reductase (EC 1.5.1.4, DHFR) as effectively as methotrexate (MTX) and also inhibits thymidylate synthetase (EC 2.1.1.45, TS). Its toxicity to cultured L1210 cells is comparable with that of MTX, and is reversed by thymidine/hypoxanthine or thymidine/folinic acid combinations. It is transported via the reduced folate pathway, but reaches higher intracellular levels than MTX. CB 3705 also inhibits DHFR and TS. Its toxicity in vitro may be reversed either by folinic acid or by thymidine alone. It is probably transported neither via the folate nor via the reduced folate pathway. Studies of the toxicology of CB 3703 in mice indicate that the drug is approximately 100-times more potent than MTX, although it has a short plasma half life. In animals bearing the L1210 ascites tumour a dose of 2 mg/kg will produce a 64% increase in life span. CB 3705 was considerably less potent, a dose of 480 mg/kg being non-toxic to tumour bearing animals and producing only a minimal increase in life span.