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L-Histidinol: Preclinical Therapeutic Studies in Combination with Antitumor Agents and Pharmacokinetic Studies in Mice¹

Pharmacology Branch [D. Z., J. P.] and Laboratory of Pharmaceutical Chemistry [L. M.], Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20892, and Southern Research Institute, Birmingham, Alabama 35205 [W. W., D. D.]

Therapeutic studies were conducted with L-histidinol, in combination with cyclophosphamide, bischloroethylnitrosourea, 5-fluorouracil, phenylalanine mustard, or cis-platinum(II)diammine dichloride, in several transplantable tumors in mice. These tumor types included murine L1210 P388 leukemias, M5076 sarcoma, mammary 16/C adenocarcinoma, human LOX melanoma, and colon HT-29 adenocarcinoma. Therapeutic benefits of adding L-histidinol to a regimen, compared to the regimen alone, were marginal. Pharmacokinetic studies indicated a rapid clearance of L-histidinol following a bolus dose (250 mg/kg i.p.), peak plasma concentration of 200 µg/ml (1.4 mM), and ß phase t of 12.6 min. Maximum tolerable plasma steady state concentrations with a 24-h infusion (2000 mg/kg/24 h) were no greater than 25 µg/ml (0.18 mM).

¹ National Cancer Institute, Division of Cancer Treatment, Contracts N01-CM-73726 and N01-CM-67903 were used to obtain data for this manuscript.

² To whom requests for reprints should be addressed, at Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, 9000 Rockville Pike, Executive Plaza North, Room 841, Bethesda, MD 20892.

Received 1/27/92. Accepted 4/20/92.