nsc-366140 and Pancreatic-Neoplasms

Pyrazoloacridine (PZA) is an acridine derivative selected for clinical development because of broad pre-clinical antitumor activity and solid tumor selectivity. Phase I evaluations with PZA have demonstrated predictable toxicity and suggested clinical efficacy. A phase II trial in patients with previously untreated advanced pancreatic cancer was conducted.. PZA was administered at a dose of 750 mg/m2 intravenously over 3 hours every 21 days. Seventeen patients were treated receiving a total of 46 courses of PZA.. Of the 15 patients evaluable for response, no responses were observed (0% response rate, 95% confidence interval 0-22%). Major toxicities directly attributable to PZA included moderate neutropenia and mild neurotoxicity.. PZA at this dose and schedule of administration was inactive in patients with pancreatic carcinoma.

Topics: Acridines; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Leukopenia; Male; Middle Aged; Neutropenia; Pancreatic Neoplasms; Pyrazoles; Thrombocytopenia; Treatment Outcome

Pyrazoloacridine (PZA) is a newly developed anticancer agent currently undergoing clinical trials. Its mode of action has not been elucidated but the presence in its chemical structure of a 5-nitro functional group and its activity against oxygen-deficient cancerous cells argue in favor of enzymatic nitro reduction as a possible pathway for its antitumor activity. In order to assess the involvement of the nitro functionality in PZA activity, as well as to determine other metabolic products, a pharmacological and chemical study of PZA was designed.. Urine and stool samples were collected from mice before and after treatment with PZA. Samples were fractionated using chromatographic methods and then evaluated using mass spectrometry (MS). One of the characterized metabolites was synthesized and tested in vitro and in vivo for anticancer activity.. One major fraction from mouse stool was initially characterized by MS as the 5-aminopyrazoloacridine (5-APZ). This compound was chemically synthesized by catalytic hydrogenation of PZA was stabilized as the hydrochloride salt. 5-APZ was marginally cytotoxic in vitro and was inactive in vivo against a tumor cured by PZA (Panc 03).. Bioreduction of the nitro group to an amine compound from PZA represents a pathway in the metabolic sequence of PZA. The inactivity of the chemically generated amine product does not provide conclusive evidence that this pathway is not involved in the cytotoxicity of PZA because other intermediates in the nitro reduction pathway may have a role in the activity of PZA. In particular, the hydroxylamine derivative of PZA could give answers to the involvement of this pathway in PZA cytotoxicity.

Topics: Acridines; Animals; Antineoplastic Agents; Chromatography, High Pressure Liquid; Feces; Male; Mass Spectrometry; Mice; Neoplasms, Experimental; Oxidation-Reduction; Pancreatic Neoplasms; Pyrazoles; Tumor Cells, Cultured

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.

Topics: Acridines; Adenocarcinoma; Animals; Antineoplastic Agents; Carcinoma, Intraductal, Noninfiltrating; Cell Survival; Colonic Neoplasms; 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; Pyrazoles; Tumor Cells, Cultured