Shih-Fong Chen

Preclinical activity of an i.v. formulation of rubitecan in IDD-P against human solid tumor xenografts.

An i.v. formulation of rubitecan (9-nitrocamptothecin) was evaluated in five human solid tumor xenograft models. Rubitecan in IDD-P™, a particulate suspension of the insoluble analog, produced significant tumor growth delay in athymic nude mice bearing A375 melanoma, and MX-1 breast, SKMES non-small-cell lung, Panc-1 pancreatic and HT29 colon carcinomas. The activity of i.v. rubitecan was similar or somewhat superior to those of i.p. regimens with the reference drugs, irinotecan and topotecan. Tumor sensitivity to rubitecan in IDD-P was MX-1>A375>SKMES >Panc-1>HT29. Some complete regression responses were seen with MX-1, A375 and SKMES tumors treated with 2.5 mg/kg on a schedule of two 5-day dosing cycles separated by 2 drug-free days. In nude mice, the MTD of rubitecan in IDD-P lies between 2 and 2.5 mg/kg on this schedule; antitumor efficacy was achieved with doses between 2.5 and 1.25 mg/kg. Dosing with 6.6 mg/kg rubitecan in IDD-P on intermittent schedules (4- or 7-day intervals) was tolerated, but less efficacious, when tested in the A375 model. The good responses obtained with rubitecan in IDD-P suggest it could be used clinically in circumstances where an i.v. formulation offers advantages to oral or aerosol formulations.

Preclinical Studies with Brequinar Sodium: A Novel Anticancer Agent

A novel, substituted 4-quinolinecarboxylic acid, 2-(4-cyclohexylphenyl)-6-fluoro-3-methyl -4-quinolinecarboxylic acid, NSC 339768, was submitted to, and was found active in the National Cancer Institutes Developmental Therapeutics Program. Based on this finding, an analog synthesis program was initiated in our program; over 200 derivatives of NSC 339768 were prepared (1). One of these analogs, 6-fluoro-2-(2′-fluoro-1, 1′-biphenyl-4-yl)-3- methyl-4-quinolinecarboxylic acid sodium salt, (NSC 368390, DuP 785, brequinar sodium, Figure 1), was selected for further study because of its antitumor activity and water solubility. This paper reviews the preclinical antitumor activity of brequinar sodium against murine tumors and human carcinomas xenografted in nude mice, the mechanism of action of the agent, and the structure activity relationship of this class of 4-quinolinecarboxylic acids.