nsc-366140 and Neoplasms

Topics: Acridines; Animals; Antineoplastic Agents; Drug Design; Humans; Neoplasms; Pyrazoles

Pyrazoloacridine (PZA, NSC366140, PD115934) is an acridine derivative currently undergoing clinical evaluation. In preclinical testing, PZA has shown selectivity for solid tumor cell lines, activity in hypoxic, noncycling, and multidrug-resistant cell lines, and synergy with cisplatin in a variety of lung cancer cell lines. In early phase I clinical studies PZA has shown modest activity in ovarian, cervical, and colon cancer. The purpose of the present study was threefold: to determine the maximally tolerated doses of the combination of PZA (3-h infusion) and cisplatin administered with and without Filgrastim (G-CSF) (Amgen, Thousand Oaks, CA) every 3 weeks in untreated or minimally pretreated patients, to describe and quantify the clinical toxicities of combination chemotherapy with PZA and cisplatin, and to evaluate the effects of drug sequencing on the toxicity profile and pharmacologic behavior of PZA. The starting doses in this dose-escalation trial were PZA 400 mg/m2 as a 3-h intravenous infusion and cisplatin 50 mg/m2 as a 1 mg/min intravenous infusion. The sequence of drugs was alternated with each successive course in each patient treated. Twenty-one patients with refractory solid tumors received 43 courses of therapy through four dose levels. Neutropenia was dose-limiting and defined the maximum tolerated dose of PZA 400 mg/m2 and cisplatin 50 mg/m2 without G-CSF support. With G-CSF support, nausea and vomiting were dose-limiting. The maximum tolerated and recommended doses for further study of this combination are PZA 600 mg/m2 over 3 h and cisplatin 50 mg/m2 followed by G-CSF support. Pharmacokinetic analysis showed that sequence does not impact on the pharmacokinetics of PZA when given in combination with cisplatin.

Topics: Acridines; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Pyrazoles; Recombinant Proteins; Time Factors; Treatment Outcome

Pyrazoloacridine (PZA) is an investigational nucleic acid binding agent that inhibits the activity of topoisomerases I and II through a mechanism distinct from other topoisomerase poisons. PZA shows schedule-independent cytotoxicity against tumor cells, whereas host toxicity is greater with shorter infusions. We assessed the clinical toxicities and pharmacologic effects of PZA given as a 24-h i.v. infusion weekly for 3 of 4 weeks.. Thirty-two adult patients with solid tumors received PZA at five dose levels (100-351 mg/m(2)). Plasma samples were obtained at the end of the PZA infusion at all of the dose levels, with extended sampling in a cohort treated at the recommended dose.. Dose-limiting granulocytopenia and mucositis occurred in 2 of 6 patients at 351 mg/m(2), but lower doses were well tolerated. No responses were seen, but 28% had stable disease for > or =3 months. Plasma levels strongly correlated with the degree of granulocytopenia. Extended pharmacokinetics in 7 patients treated with 281 mg/m(2) indicated the following averages: maximum plasma level, 1.6 microM; area under the plasma concentration-time curve, 56 microM.h; terminal half-life, 27 h; urinary recovery, 17% over 72 h. DNA fragmentation in post-PZA bone marrow mononuclear cells was seen in 9 of 28 samples (all at > or =281 mg/m(2)).. Unlike other schedules of PZA, neurotoxicity and thrombocytopenia were not problematic with a weekly 24-h infusion of PZA. The recommended Phase II dose is 281 mg/m(2), which was well tolerated. Both end of infusion plasma levels and presence of DNA damage correlated with granulocyte toxicity.

Topics: Acridines; Adult; Aged; Aged, 80 and over; Agranulocytosis; Antineoplastic Agents; Apoptosis; Drug Administration Schedule; Female; Gastrointestinal Diseases; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Pyrazoles

Pyrazoloacridine (PZA) is the first of a new class of rationally synthesized acridine derivatives to undergo clinical testing as an anticancer agent. We previously demonstrated cytotoxic synergy between combinations of PZA and platinum compounds. Subsequent studies revealed that PZA inhibits removal of platinum-DNA adducts in cultured A549 cells. Based on these results, we undertook a phase I study of the combination of PZA and carboplatin (CBDCA).. Twenty-eight patients received 76 28-day courses (median 2.5, range 1-6) of CBDCA (30-minute infusion) followed by PZA (3-hour infusion), through six dose levels [PZA/CBDCA] (200/AUC 3, 400/AUC 3, 400/AUC 4, 400/AUC 5, 500/AUC 5, 600/AUC 5 mg/m2/AUC). Pharmacokinetic analyses were performed to evaluate the disposition of PZA. Retention of platinum-DNA adducts in peripheral blood mononuclear cells of patients was also evaluated.. The most common and dose-limiting toxicity was myelosuppression, consisting of neutropenia and leukopenia. Non-hematologic toxicities of anorexia, nausea and stomatitis were mild to moderate. In six patients evaluated at the MTD, CBDCA did not appear to affect the pharmacokinetics of PZA. One patient with malignant melanoma had a partial response. Disease stabilization for greater than 4 courses of treatment occurred in 4 patients.. The combination of PZA and CBDCA was well tolerated and may have utility in some tumor types.

Topics: Acridines; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carboplatin; DNA Adducts; Drug Interactions; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasms; Neutropenia; Platinum; Pyrazoles

To define the maximum-tolerated dose (MTD), quantitative and qualitative toxicities, recommended phase II dose, and pharmacokinetics of pyrazoloacridine (PZA) administered as a 1- or 24-hour infusion in children and young adults with refractory cancers.. Twenty-two patients received PZA as a 1-hour infusion at doses of 380 mg/m2 (n = 3), 495 mg/m2 (n = 6), 640 mg/m2 (n = 6), and 835 mg/m2 (n = 7). An additional four patients received PZA as a 24-hour infusion at the MTD (640 mg/m2) for the 1-hour infusion schedule. Plasma samples were obtained for pharmacokinetic analysis in 17 patients. PZA concentration in plasma was measured by reverse-phase high-performance liquid chromatography (HPLC). A two-compartment pharmacokinetic model was fit to the PZA plasma concentration data.. On the 1-hour infusion schedule, dose-limiting myelosuppression (neutropenia more than thrombocytopenia) was observed in two of seven patients at the 835-mg/m2 dose level. Myelosuppression did not appear to be ameliorated by prolonging the infusion to 24 hours. Nonhematologic toxicities were minor. Significant neurotoxicity, which was dose-limiting in adults treated with a 1-hour infusion of PZA, was observed in one patient treated at 640 mg/m2, but was not dose-limiting. There was marked interpatient variability in plasma PZA concentrations at all dose levels. The pharmacokinetic profile of PZA was characterized by an initial rapid decline (alpha half-life [t(1/2)alpha], 0.5 hours) followed by a prolonged elimination phase (t(1/2)beta, 30 hours). The volume of distribution at steady-state (Vd(ss)) was 700 L/m2 and the clearance was 300 mL/min/m2. There was no evidence of dose-dependent clearance. The area under the PZA concentration-time curve (AUC) correlated poorly with dose and was more predictive of the degree of myelosuppression than was PZA dose.. PZA administered as 1- or 24-hour infusion is well tolerated by children and young adults. The dose-limiting toxicity (DLT) is myelosuppression. Neurotoxicity is not prominent in this age group. There was marked interpatient variation in plasma concentrations of PZA. The recommended dose for phase II studies is 640 mg/m2.

Topics: Acridines; Adolescent; Adult; Antineoplastic Agents; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Infant; Infusions, Intravenous; Male; Neoplasms; Neutropenia; Pyrazoles; Thrombocytopenia

The pyrazoloacridine (PZA) analogue NSC366140 (PD115934) entered clinical trial based on unique preclinical characteristics including solid tumor selectivity in vitro, marked antitumor activity in vivo against murine solid tumors, selectivity against noncycling cells, and activity against multidrug-resistant tumor cells. After identification of the pre-clinical efficacy and an acceptable toxicity profile, a Phase I study of PZA was carried out. A total of 28 patients was entered and received a total of 67 treatment courses. The drug was administered via a 1-h infusion every 21 days. The starting dose was 30 mg/m2 with 2-fold dose escalations through 480 mg/m2. The next dose escalation was 50%, to 720 mg/m2. Grade I through grade IV toxicities were observed. Since no dose-limiting toxicities were observed at 480 mg/m2, and up to grade IV toxicities were observed at 720 mg/m2, an intermediate dose, 600 mg/m2, was evaluated. Dose-limiting toxicities at 720 mg/m2 were hematological (grade III and IV neutropenia) in four of six patients and neurological (up to grade III cerebral toxicities, including restlessness, dizziness, agitation/anxiety, personality changes, and nightmares, as well as myoclonus) in three of six patients treated. The pharmacokinetic parameters which helped predict these toxicities included area under the curve and peak plasma level. Pharmacokinetic studies showed interpatient variations in all parameters studied. The mean area under the curve levels of PZA at the highest two dose levels in patients were near the level detected in mice at their maximum tolerated total dose. The recommended starting dose for Phase II trials using this schedule is 600 mg/m2.

Topics: Acridines; Adult; Aged; Antineoplastic Agents; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Leukopenia; Male; Middle Aged; Nausea; Neoplasms; Pyrazoles; Vomiting

The cytotoxicity and mechanism of action of a series of substituted 9-aminoacridines is evaluated using topoisomerase I and cancer cell growth inhibition assays. In previous work, compounds of this type were shown to catalytically inhibit topoisomerase II, leading to a G1-S phase arrest of the cell cycle and apoptosis in pancreatic cancer cells in vitro and in vivo. The present study expands the potential utility of these compounds in the development of cancer therapeutics by showing that these compounds inhibit proliferation of cell lines derived from the nine most common human cancers. Further results show that at least one of the compounds effectively stabilizes topoisomerase I-DNA adduct formation in intact cells. RNA interference experiments, however, indicate that this interaction does not contribute to the drug-induced killing of cancer cells indicating the compounds may be non-lethal poisons of topoisomerase I.

Topics: Acridines; Aminacrine; Antineoplastic Agents; Cell Line; Chemistry, Pharmaceutical; DNA Topoisomerases, Type I; Dose-Response Relationship, Drug; Doxorubicin; Drug Design; Drug Screening Assays, Antitumor; Etoposide; Humans; Models, Chemical; Neoplasms; RNA, Small Interfering