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

Abstract

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.

• Authors: P LoRusso, A J Wozniak, L Polin, D Capps, W R Leopold, L M Werbel, L Biernat, M E Dan, T H Corbett
• Journal: Cancer research (Cancer Res) Vol. 50 Issue 16 Pg. 4900-5 (Aug 15 1990) ISSN: 0008-5472 [Print] United States
• PMID: 2165850 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Acridines
• Antineoplastic Agents
• Pyrazoles
• NSC 366140

Topics

• Acridines (pharmacology, therapeutic use)
• Adenocarcinoma (drug therapy)
• Animals
• Antineoplastic Agents (therapeutic use)
• Carcinoma, Intraductal, Noninfiltrating (drug therapy)
• Cell Survival (drug effects)
• Colonic Neoplasms (drug therapy)
• Drug Evaluation, Preclinical
• Drug Screening Assays, Antitumor
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Inbred Strains
• Pancreatic Neoplasms (drug therapy)
• Pyrazoles (pharmacology, therapeutic use)
• Tumor Cells, Cultured (cytology, drug effects)