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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Further evidence for a basis of selective activity and relative responsiveness during antifolate therapy of murine tumors.

A greater persistence of unbound (exchangeable) drug in tumor cells versus drug-limiting normal tissue (proliferating epithelium of small intestine) correlates with the therapeutic effects of various antifolates against a group of murine tumors. After approsimate equimolar doses (3 mg/kg i.p.) of methotrexate (MTX) methasquin (MQ), aminopterin, and N-([2,4-diamino-5-chloro-6-quinazolinyl) methyl]-amino)benzol)-L-glutamate (5-Cl-deaza-AM), total accumulation in small intestine was vie- to eight-fold greater than the dihydrofolate reductase content. Free drug persisted for less than 4 hr (MTX), 16 hr (MQ), 30 hr (aminopterin),and 48 hr (5-Cl-deaza-AM). Overall drug accumulation in L121O cells was greater (12- to 40-fold enzyme level), and drug persistence above enzyme level was more prolonged in the case of MTX (24 hr),MQ (32 hr), and 5-Cl-deaza-AM (greater than 48 hr). Persistence of aminopterin was similar to that seen in small intestine. After the same dose of each drug s.c., the results were similar in small intestine. In L121o cells, however, the total drug accumulation was much lower, but the relative persistence of each was similar to that seen after an i.p. dose. After a single optimal therapeutic dose (3, 0.75, 0.3, and 0.1 mg/kg i.p. for MTX, MQ, aminopterin, and 5-Cl-deaza-AM every other day), accumulation of each drug in for no more than 4 hr. In L121O cells, maximal accumulation of each drug also varied, but persistence differed in accordance with the relative therapeutic effectiveness of each (9 hr for 5-Cl-deaza-AM, 12 hr for aminopterin, and more than 20 hr for MTX amd MQ).[1]


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