Showing papers on "Mitoxantrone published in 1984"

Interactions of the antitumor agents mitoxantrone and bisantrene with deoxyribonucleic acids studied by electron microscopy.

Abstract: The interactions of the low cardiotoxic antitumor agents 1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9, 10-anthracenedione (mitoxantrone) and 9,10-anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazoyl-2-yl)hydrazone] (bisantrene) with pBR322 and PM2 DNA have been examined by electron microscopy. Direct evidence was obtained for intercalative binding of both drugs, with mitoxantrone causing a 13% average length increase in pBR322 corresponding to approximately 580 drug molecules per circle at saturation and bisantrene causing an 11% increase in length corresponding to approximately 480 drug molecules bound per circle. Considerations of the known GC preference for non-nearest neighbor binding of the drugs and inspection of the known sequence of pBR322 suggest that the available intercalation sites are occupied and that additional external electrostatic binding of the cationic drugs also occurs. An apparent difference in behavior of mitoxantrone as compared with that of bisantrene in causing no net increase in length of supercoiled pBR322 was shown to be attributable to an offsetting compaction due to extensive supercoiling by mitoxantrone molecules. This conclusion was confirmed by independent experiments with PM2 covalently closed-circular DNA--both native, negatively supercoiled and relaxed--with calf thymus topoisomerase, using ethidium for comparison. Ethidium caused a 21.3 +/- 3.6% length increase in nicked, open-circular PM2-DNA, or 2100 molecules bound per 10,300 base pairs. Mitoxantrone caused a 16.6% length increase in nicked PM2-DNA equivalent to approximately 1700 drug molecules per circle. Electron microscopic measurements on relaxed PM2-DNA with progressively increasing proportions of mitoxantrone (from 1.4:1 to 14:1 drug molecules per base pair) revealed the onset of formation of lacelike networks of DNA circles linked together. This phenomenon, which is not produced by bisantrene, is attributed to inter-DNA links by the charged side arms of mitoxantrone and is in accord with previous reports that mitoxantrone causes severe compaction and distortion of chromatin. Electron microscopic examination of the interaction of six additional mitoxantrone derivatives, two of which produced lacelike DNA networks, revealed strict structural requirements for this phenomenon.

Mitoxantrone: An active new agent in the treatment of advanced breast cancer

Abstract: Sixty-five patients with advanced breast carcinoma were treated with mitoxantrone, an anthracenedione with structural similarities to adriamycin. The series included 26 patients who had received no prior chemotherapy. Treatment was given in a dose of 12-14 mg/m2 by IV infusion, repeated every 3 weeks. Sixty-two patients were evaluable for response, but all were evaluable for toxicity. One (2%) achieved a complete response and 18 (29%) a partial response (overall response rate 31%). The response rate in patients who had received no prior chemotherapy was 35%, vs 22% in previously treated patients. The median duration of response was 10 months (range 3.5-18.5 months). Two responders had previously failed to respond to adriamycin, and a third responder subsequently failed to respond to adriamycin. Neutropenia was the most frequently seen toxicity, with a WBC of less than 2,000/mm3 seen in 26 patients (40%), eight of whom (12%) had a neutropenic infection. Thrombocytopenia (less than 100,000/mm3) occurred in 12 patients (18%), but in three of these only after at least 6 months of treatment. Two patients developed readily reversible cardiac failure after prolonged treatment (11-13 months). Other toxicities were in general mild, and the drug was well tolerated: severe alopecia occurred in only one patient. Mitoxantrone is an active well-tolerated agent in the treatment of advanced breast carcinoma, but the risk of neutropenia requires careful supervision. The long-term risk of cardiotoxicity cannot yet be fully assessed.

Southwest Oncology Group study of Mitoxantrone for treatment of patients with advanced squamous cell carcinoma of the head and neck.

Abstract: Twenty-two patients are evaluable for response in a Phase II trial of Mitoxantrone for advanced squamous cell carcinoma of the head and neck. One patient had a partial response, one an improvement and twenty had progressive disease. The major toxicities were leukopenia and thrombocytopenia. There was no significant antitumor activity of Mitoxantrone in this group of patients with head and neck cancer, most of whom were previously treated with radiation and chemotherapy.

Relation of in vitro colony survival to clinical response in a prospective trial of single-agent chemotherapy for metastatic melanoma.

Abstract: We have used the effect of therapeutic agents on clonogenic growth in agar to discriminate between active and inactive agents for malignant melanoma. We report a prospective study of single-agent chemotherapy for metastatic melanoma. Forty-five separate in vitro/in vivo correlative trials were conducted in 34 patients. A number of agents were used in these evaluations, including actinomycin D, Amsacrine, bisantrene, mitoxantrone, BCNU, vinblastine, vindesine, 5-fluorouracil, MGBG, etoposide, interferon, tamoxifen, and 13-cis-retinoic acid. At the "cut-off" concentration, a colony survival less than 30% was designated as "sensitivity" and greater than 30% as "resistance." Clinical sensitivity was designated to include complete, partial, and mixed responses and was predicted in eight of 18 trials (44%). Clinical resistance (nonresponse) was predicted correctly in 24 of 27 cases (89%). Using Fisher's exact test the association of in vitro and in vivo results was significant (P = .05). These results offer further support for the concept that clonogenic assays may help select useful agents for clinical trials in metastatic melanoma.

Use of a human tumor cloning system to evaluate analogs of methotrexate and mitoxantrone.

Abstract: We have utilized a human tumor cloning system to compare the antitumor activity of trimetrexate ( TMQ ), a new dihydrofolate reductase inhibitor, and ametantrone , a new anthracenedione, with that of analogs already in clinical trial (methotrexate and mitoxantrone). Sixty-nine of 136 tumors plated for the TMQ study and 84 of 228 tumors plated for the ametantrone study were evaluable for drug-sensitivity assays. The overall in vitro response rates (defined as a less than or equal to 50% survival of tumor colony-forming units) for TMQ were 20% and 23% at 0.1 and 1 microgram/ml, respectively; for ametantrone they were 13%, 21%, and 26% at 0.1, 1, and 10 micrograms/ml, respectively. The overall in vitro activity for both new compounds was similar to that of their clinically used analogs, but TMQ was active in eight of 47 methotrexate-resistant specimens and ametantrone in nine of 62 mitoxantrone-resistant specimens. A comparison of these in vitro results with the results of phase II clinical trials with both drugs should allow an evaluation of the utility of the human tumor cloning system for predicting clinical antitumor activity of analogs of currently available antineoplastic agents.

Mitoxantrone metabolism in the isolated perfused rat liver

Abstract: The hepatobiliary pharmacokinetics of mitoxantrone, a new anthracenedione derivative, was studied in the isolated perfused rat liver. Mitoxantrone was administered in doses of 0.2 and 0.4 mg/kg body weight. Multiple bile samples were obtained for 4 hours. Mitoxantrone and three metabolites were separated by high-performance thin-layer chromatography (HPTLC) and measured at 610 nm. Following 0.2 mg mitroxantrone/kg body wt, 25.8%±2.6% of the administered dose was excreted in the bile during 4 h, the major metabolite M1 accounting for 80% of this. After 0.4 mg mitoxantrone/kg body wt the amounts excreted were lower and light microscopic examination showed disseminated areas of cell necrosis.

Mitoxantrone in epithelial carcinoma of the ovary. A Southwest Oncology Group study.

Abstract: THIRTY-NINE PATIENTS WITH ADVANCED HEAVILY pretreated epithelial carcinoma of the ovary were treated with mitoxantrone (dihydroxyanthracenedione hydro-chloride). Twenty-five patients were started at a dose of 12 mg/m2 q 21d and 13 patients, with compromised bone marrow, at a dose of 10 mg/m2 q 21d. Two stable responses (6%) occurred in 31 fully evaluable patients. The median duration of survival was 17 weeks. The principal toxicity, hematopoietic (primarily leukopenia), was mild and well tolerated. We conclude that mitoxantrone is a relatively inactive drug in the treatment of epithelial ovarian carcinoma.