Antitumor efficacy of PD115934 (NSC 366140) against solid tumors of mice

• Published in: Cancer research (Chicago, Ill.) Vol. 50; no. 16; pp. 4900 - 4905
• Main Authors: LORUSSO, P, WOZNIAK, A. J, POLIN, L, CAPPS, D, LEOPOLD W. R, WERBEL, L. M, BIERNAT, L, DAN, M. E, CORBETT, T. H
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.08.1990
• Subjects: Acridines - pharmacology; Acridines - therapeutic use; Adenocarcinoma - drug therapy; Animals; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Carcinoma, Intraductal, Noninfiltrating - drug therapy; Cell Survival - drug effects; Chemotherapy; Colonic Neoplasms - drug therapy; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred Strains; Pancreatic Neoplasms - drug therapy; Pharmacology. Drug treatments; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Tumor Cells, Cultured - cytology; Tumor Cells, Cultured - drug effects; Antineoplastic agent; Therapeutic efficiency; Human; Intravenous administration; Toxicity; Rodentia; Cytotoxicity; In vitro; In vivo; Vertebrata; Mammalia; Mouse; Animal; Tumor
• ISSN: 0008-5472; 1538-7445

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 greater than 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.