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Phase I Evaluation and Pharmacokinetics of Aziridinylbenzoquinone Using a Weekly Intravenous Schedule¹

Department of Internal Medicine, Division of Oncology, Wayne State University, Detrolt, Michigan 48201

Quinone derivatives have shown intensive antitumor activity in a broad variety of neoplasias. Aziridinylbenzoquinone is designed to have adequate lipid solubility to attain useful drug concentrations in the central nervous system.

A Phase I study of aziridinylbenzoquinone was conducted in 32 patients with advanced solid cancers. The drug was given as a slow i.v. injection on Days 1, 8, 15, and 22 of a 42-day cycle with a 2-week rest. Five dose levels ranging from 5 to 20 mg/sq m were studied, with 3 to 10 patients treated at each level; a total of 156 doses were administered. The major toxicity was myelosuppression with the median nadir in platelet and white blood cells occurring at Days 15 to 27 of the cycle, and first appearing at doses greater than 10 mg/sq m. Anemia was first seen at the 10-mg/sq m dose level, occurring between Days 22 and 40.

Nonmyelosuppressive toxic effects included nausea and vomiting, anorexia, diarrhea, stomatitis, slight alopecia, and transient fever. The highest tolerated dose was 20 mg/sq m, the recommended dose for Phase II studies. Plasma and urine pharmacoknetics were studied in 17 patients by a high-pressure liquid chromatography method. Plasma decay curves could be fitted to a two-compartment open-system model with an overall average and ß half-life values of 10.5 ± 6.28 min and 16.90 ± 8.63 (S.D.) hr. Aziridinylbenzoquinone levels were determined in urine samples of 12 patients, but less than 0.1% of the dose was excreted in the 0- to 4-hr sample of two patients, and none was detected in the urine of 10 patients.

¹ This study was supported by Contract N01-CM-97279 with the Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Md. 20205.

² Supported by Grant Schi 209/1-1 from the Deutsche Forschungsgemeinschaft, Bonn, Federal Republic of Germany.

³ To whom requests for reprints should be addressed, at Department of Internal Medicine, Division of Oncology, Wayne State University, 4201 St. Antoine, Detroit, Mich. 48201.

Received 2/17/82. Accepted 4/19/83.