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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1988 Apr;79(4):509–516. doi: 10.1111/j.1349-7006.1988.tb01620.x

Pharmacokinetic Approach to Rational Therapeutic Doses for Human Tumor‐bearing Nude Mice

Makoto Inaba 1, Tomowo Kobayashi 1,†, Tazuko Tashiro 1, Yoshio Sakurai 1,‡
PMCID: PMC5917508  PMID: 3133339

Abstract

To improve clinical predictability from therapeutic results of various antitnmor agents in human tumor/nude mouse models it seems to be important to use a dose pharmacokinetically equivalent to the clinical dose. Thus, we attempted to find the dose of a given drug that can reproduce in the nude mouse a plasma level similar to that seen in human patients treated with an effective dose of the drug based on comparative pharmacokinetic studies between man and nude mouse. As a result, those of 3 alkylating agents, mitomycin C, 3‐[(4‐amino‐2‐methyl‐5‐pyrimidinyl)methyl]‐l‐(2‐chloroethyl)‐l‐nitrosourea (ACNU) and cyclophosphamide, and those of 2 antimitotic agents, vincristine and vinblastine, were estimated to be one‐fourth or one‐fifth of their maximum tolerated doses (MTD's). On the other hand, in the case of adriamycin, its MTD was approxmately equivalent to its clinical dose pharmacokinetically. In contrast, clinically equivalent doses of 2 antimetabolites tested, 5‐fluorouracil and methotrexate, were significantly greater than their MTD's; i.e., their plasma levels did not reach the effective clinical ones even when their MTD's were administered to the nude mice. These results suggest that the antitumor effects of mostv antitumor agents are over‐ or underestimated in this model when MTD's are used as a therapeutic dose, and indicate that the use of clinically equivalent doses determined pharmacokinetically isdesirable.

Keywords: Antitumor agents, Human tumor, Nude mouse, Plasma level, Clinically equivalent dose

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