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Antitumor Efficacy of PD115934 (NSC 366140) against Solid Tumors of Mice¹

Department of Internal Medicine, Division of Hematology and Oncology [P. L., L. P., L. B., T. H. C.], and Department of Pathology [M. E. D.], Wayne State University School of Medicine, Detroit, Michigan 48202-0188; Veterans' Administration Medical Center, Division of Hematology and Oncology, Allen Park, Michigan 48101 [A. J. W.]; and Parke-Davis Pharmaceutical Research Division, Ann Arbor, Michigan 48105 [W. R. L., L. M. W., D. C.]

PD115934 (NSC 366140) is a soluble pyrazoloacridine derivative presently undergoing preclinical toxicology evaluation with the anticipation of Phase I human investigation. The agent displayed both human and murine solid tumor selectivity in vitro in a soft agar disk diffusion assay, relative to its activity against murine L1210 leukemia. In vivo it was highly active against solid tumors colon adenocarcinoma 38 and pancreas ductal carcinoma 03, which was consistent with the cellular cytotoxicity seen in the disk diffusion assay. A log cell kill of >4.0 was demonstrated in vivo against both models.

PD115934 was administered by both bolus and infusional therapy. After completion of these trials, it was determined that this compound was a schedule category III agent, i.e., a schedule-independent agent with peak plasma level toxicity. The main toxicity encountered with infusional therapy was myelosuppression. With bolus therapy, central nervous system toxicities were dose limiting. On the basis of our preclinical infusion studies, we recommend a 2-h infusion twice weekly in humans in order to obtain a total dose of 360 mg/m² over 8 weeks.

¹ Supported by NIH Grants CA-45962 and CA-43886, the Ben Kasle Trust Fund for Cancer Research, and a grant from the Veterans' Administration Research Funds.

² To whom requests for reprints should be addressed, at Division of Hematology and Oncology, Harper Hospital, 5-Hudson, P. O. Box 02188, Detroit, MI 48202-0188.

Received 10/10/89. Revised 4/27/90.

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