nsc-366140 and Ovarian-Neoplasms

Acridine compounds are believed to exhibit anti-cancer cytotoxic effects because of interactions with both DNA and RNA. Pyrazoloacridine (PZA) (NSC No. 366140) is a 9-methoxyacridine compound that has demonstrated activity in some patients with solid tumors. The Gynecologic Oncology Group (GOG) performed a phase II trial of PZA to determine the response rate of this agent in patients with recurrent platinum-sensitive ovarian cancer.. Patients with recurrent ovarian cancer who experienced a progression-free interval of greater than 6 months after response to platinum-based chemotherapy are defined as platinum sensitive by the GOG and were eligible for this trial. PZA was administered at a dose of 750 mg/m2 intravenously over 3 h every 3 weeks.. Among 42 evaluable patients, there was 1 (2.4%) complete response and 9 (21.5%) partial responses, including 1 patient who had a partial response after 10 courses of treatment. The major toxicity was neutropenia; severe thrombocytopenia was infrequent.. PZA demonstrates moderate activity in this chemotherapy-sensitive population, with manageable hematologic toxicity. Due to its unique mechanism of action and preclinical activity against hypoxic and noncycling cells, PZA should be considered for evaluation in combination with other active agents.

Topics: Acridines; Adult; Aged; Antineoplastic Agents; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Ovarian Neoplasms; Pyrazoles

The Gynecologic Oncology Group performed a Phase II study to determine the response rate of pyrazoloacridine (PZA) in patients with platinum-resistant ovarian cancer. PZA was administered at a dose of 750 mg/m2 intravenously over 3 hours every 3 weeks. Among 24 evaluable patients, there was 1 (4.2%) complete and 1 (4.2%) partial response. The major toxicities were hematologic. With the dose and schedule used, PZA had only modest activity in this population.

Topics: Acridines; Adult; Aged; Antineoplastic Agents; Carboplatin; Cisplatin; Drug Resistance, Neoplasm; Female; Humans; Middle Aged; Ovarian Neoplasms; Pyrazoles

To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacologic behavior of pyrazoloacridine (PZA), a novel DNA intercalator with a unique mechanism of action, on single- and multiple-dosing schedules.. PZA was administered on a single-dosing schedule as a 1- to 3-hour infusion and on a multiple-dosing schedule as a 1-hour infusion daily for 5 days to cancer patients at doses ranging from 400 to 935 mg/m2 and 40 to 180 mg/m2/d every 3 weeks, respectively.. On the single-dosing 1-hour schedule, CNS toxicity, characterized by neuropsychiatric and neuromotor effects, prompted prolongation of the infusion duration to 3 hours and led to a study of PZA on a multiple-dosing schedule. Both measures resulted in lower incidence of CNS toxicity. Neutropenia was the principal toxicity and precluded dose escalation to levels greater than 750 mg/m2 on the single-dosing (3-hour) schedule and 150 mg/m2/d x 5 (total dose, 750 mg/m2) on the multiple-dosing schedule. Thrombocytopenia, anemia, and nonhematologic effects occurred less frequently. Responses were observed in several patients with platinum- and taxane-refractory ovarian carcinoma; antitumor activity was also noted in patients with cervical and colorectal carcinomas. Significant intraindividual variability characterized by the presence of multiple drug peaks and troughs was observed in the pharmacologic studies. The maximal PZA concentrations achieved in both studies exceeded drug concentrations associated with significant cytotoxicity in preclinical studies and correlated with the occurrence of CNS toxicity.. Neutropenia is the dose-limiting toxicity on both schedules and 750 mg/m2 and 150 mg/m2/d are the recommended starting doses of PZA on single- and multiple-dosing schedules, respectively, for minimally pretreated patients in phase II studies; slightly lower doses are recommended for more heavily pretreated subjects. The favorable toxicity profile of PZA and its antitumor activity in several refractory tumors warrant broad phase II evaluations of this agent.

Topics: Acridines; Adult; Aged; Antineoplastic Agents; Central Nervous System; Colorectal Neoplasms; DNA, Neoplasm; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Intercalating Agents; Male; Middle Aged; Neutropenia; Ovarian Neoplasms; Pyrazoles; Remission Induction; Uterine Cervical Neoplasms