nsc-366140 and Prostatic-Neoplasms

There is a pressing need for new agents for the treatment of hormone-resistant prostate cancer (HRPC). Pyrazoloacridine (PZA) has antitumor activity in several in vitro and in vivo tumor systems, and was selected for testing in clinical trials by the National Cancer Institute (NCI). We conducted a phase II trial of PZA for the treatment of HRPC. Seventeen male patients with HRPC were treated with PZA at 750 mg/m2 i.v. given over a period of 3 hr every 3 weeks. Response to therapy was assessed with serial measurements of serum prostate-specific antigen (PSA) and sequential imaging studies. The 17 patients were treated and fully evaluable. One patient experienced a significant decrease in PSA, from over 10,000 ng/ml to 423 ng/ml, along with an improvement in bone scan findings. However, no other patient obtained an objective or PSA response (overall PSA response rate = 5.9%). Median survival duration was 15.3 months. Toxicity was moderate. If PSA is used as a marker of response, single-agent PZA appears to lack efficacy in the treatment of HRPC. However, the one unambiguous response, and the favorable toxicity profile observed, may warrant further evaluation of this agent.

Topics: Acridines; Aged; Antineoplastic Agents; Drug Administration Schedule; Drug Resistance, Neoplasm; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Pyrazoles; Survival Analysis

Pyrazoloacridine (PZA) is a 9-methoxy substituted acridine with a reducible nitro group. PZA has shown selective solid tumor cytotoxicity with activity against hypoxic cells, non-cycling cells and cells expressing the multidrug resistant phenotype. A high-performance liquid chromatographic (HPLC) assay was developed and validated for the determination of PZA in human plasma to support phase II clinical trials. PZA and ethyl orange, the internal standard, were isolated from human plasma by precipitating plasma proteins with methanol, and centrifuging to pellet the proteins. The resulting supernatant was injected onto a cyanopropyl HPLC column eluted isocratically with a mobile phase consisting of 125 mM ammonium acetate buffer pH 4.75-acetonitrile (76:24, v/v). A single wavelength at 460 nm was used for detection. Relative standard deviations for the assay ranged from 5.0% to 12.2% for four different drug concentrations and the limit of quantitation was 100 ng/ml. During the validation short term stability of the drug in plasma and stability of PZA on repeated freezing and thawing of plasma was evaluated. Overall recovery of PZA was 88%. This simple assay was found suitable for studying the clinical pharmacokinetics of PZA.

Topics: Acridines; Antineoplastic Agents; Chromatography, High Pressure Liquid; Circadian Rhythm; Drug Stability; Freezing; Humans; Infusions, Intravenous; Male; Osmolar Concentration; Prostatic Neoplasms; Pyrazoles; Reproducibility of Results; Sensitivity and Specificity; Temperature; Time Factors