mitonafide and Lung-Neoplasms

The new intercalative agent Mitonafide was shown in early clinical trials to be toxic to the central nervous system when administered as a short intravenous infusion, but not when given as a 120-hour continuous infusion. Thus, clinical development in different tumor types was pursued using only this administration schedule.. Forty-nine patients with previously untreated non-small cell lung cancer (NSCLC) and at least one measurable site received Mitonafide as a 120-hour continuous (5 days) infusion every 3 weeks. The starting dose was 170 mg/m2/day x 5 in the first 26 patients and 200 mg/m2/day x 5 in the remainder. Patients were evaluated for toxicity after each course and for response every two courses and remained on treatment until excessive toxicity or disease progression were observed. A special test, the "Mini-mental state", was used to assess patients' cognitive functions.. Of the 49 patients entered, 42 were evaluable for response and toxicity. Toxicity consisted mainly of myelosuppression and no neurologic side effects were observed. Only one patient presented a partial response.. Although definitively safe with this schedule of administration, Mitonafide is not active in NSCLC.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cognition; Drug Administration Schedule; Female; Humans; Imides; Infusions, Intravenous; Isoquinolines; Lung Neoplasms; Male; Middle Aged; Naphthalimides

Mitonafide is the lead compound of a new series of antitumor drugs, the 3-Nitronaphthalimides, which have shown antineoplastic activity in vitro as well as in vivo. This phase I Mitonafide study in non-small cell lung cancer using a 120-hour continuous infusion (120 h. C.I.) schedule of administration was designed to deliver the maximum amount of drug while avoiding the risk of central nervous system (CNS) toxicity, previously observed in studies with daily short (1 hour) administration schedules. Twenty patients were treated at doses ranging from 107-200 mg/m2 x 120 h. C.I. Dose-limiting toxicity with this schedule of administration was leukopenia. Other toxicities were mild or not relevant. No CNS toxicity was observed. The recommended dose for phase II C.I. Mitonafide studies is 170 mg/m2 x 120 h. C.I. in previously untreated patients. Plasma level monitoring is recommended.

Topics: Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Female; Humans; Imides; Infusion Pumps; Isoquinolines; Leukopenia; Lung Neoplasms; Male; Middle Aged; Naphthalimides

The synthesis of novel unsymmetrical bifunctional antitumor agents was accomplished by linking an imidazoacridone moiety to another polycyclic heteroaromatic moiety via linkers of various length and rigidity. These compounds bind to cellular DNA, but it is hypothesized that biological effects become manifested when the drug-DNA complexes interact with critical DNA binding proteins that are involved in repair and transcription. The most promising compound of the series, 4ad (WMC79), consists of an imidazoacridone linked to a 3-nitronaphthalimide moiety via a 1,4-dipropanopiperazine linker. It was found to be potently, but selectively, cytotoxic against colon cancers (GI(50) = 0.5 nM, LC(50) = 32 nM) and leukemias (GI(50) = 3.5 nM, LC(50) = 33 nM). Compound 4ad, which appears to be a candidate for further development as an anticancer drug, kills sensitive cells by induction of apoptosis. It also showed significant in vivo activity against HCT-116 colon cancer xenografts in nude mice. Other compounds in the series also exhibited antitumor properties, but they were significantly lower than that of 4ad.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Carcinoma, Small Cell; Cell Line, Tumor; Cell Survival; Colonic Neoplasms; DNA Fragmentation; DNA, Neoplasm; Female; HL-60 Cells; Humans; Lung Neoplasms