detorubicin and Heart-Diseases

Between January 1981 and December 1983, a prospective therapeutic trial of detorubicin (14-diethoxyacetoxy-daunorubicin [DTR]) was conducted in 40 patients with histologically proven malignant mesothelioma (MM). DTR was given intravenously at 40 mg/m2 on days 1, 2, and 3 for five 21-day cycles, then 40 mg/m2 once every 21 days. Thirty-five patients (32 with pleural MM, 3 with peritoneal MM) were eligible. The overall median survival from onset of chemotherapy was 17 months. Complete relief from chest pain was observed in 8 of 15 cases (53%). Of 21 patients with measurable disease, there were 2 complete responses (10%) and 7 partial responses (33%). Median duration of response was 30 weeks. Congestive cardiac failure developed in two patients after 1100 and 1600 mg/m2 of DTR, respectively. Hematologic toxicity was moderate. This study demonstrates that DTR is effective against MM.

Topics: Adult; Aged; Alopecia; Bone Marrow; Clinical Trials as Topic; Daunorubicin; Female; Heart Diseases; Humans; Male; Mesothelioma; Middle Aged; Nausea; Peritoneal Neoplasms; Pleural Neoplasms; Prospective Studies; Vomiting

A phase II study of detorubicin, the semisynthetic 14-diethoxyacetoxy ester of daunorubicin, was conducted in 42 patients with metastatic melanoma. The drug was administered in a dose range of 120 to 180 mg/m2 and repeated at 3-week intervals. One clinical complete remission (soft tissue) and seven partial responses (three visceral and four soft tissue) were observed among the 22 patients who had undergone no prior chemotherapy, a complete and partial response rate of 36%. The duration of response varied from 2 to 27 months with a median of 10 months. There were also four (19%) minor responses (one visceral and three soft tissue). In contrast, among the 20 patients who had undergone prior chemotherapy treatment, only three patients showed a minor response. General toxicities were acceptable and were similar to those of Adriamycin (Adria Laboratories, Columbus, Ohio). Cardiac toxicity was evaluated by cardiac biopsy and radionuclide scan. Cardiac biopsy changes were identical to those observed with Adriamycin and were progressive with cumulative dose. One patient had a high-grade biopsy at a cumulative detorubicin dose of 1,420 mg/m2. Similarly, a trend of decreasing ejection fraction with cumulative dose was noted. Only one patient developed congestive heart failure at a cumulative dose of 1,290 mg/m2, that was well compensated with digoxin and diuretics. In contrast to Adriamycin, detorubicin has shown activity in previously untreated patients with metastatic melanoma.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Daunorubicin; Drug Evaluation; Electrocardiography; Female; Heart; Heart Diseases; Humans; Leukopenia; Lung Neoplasms; Lymphatic Metastasis; Male; Melanoma; Middle Aged; Myocardial Contraction; Skin Neoplasms; Stroke Volume; Thrombocytopenia

Topics: Acute Disease; Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Bone Marrow; Cytarabine; Daunorubicin; Drug Administration Schedule; Drug Therapy, Combination; Heart Diseases; Humans; Leukemia; Middle Aged; Naphthacenes

Six anthracycline antibiotics with demonstrated antitumor activity in human or experimental tumor systems were studied. The purpose of this investigation was to compare the cardiotoxic potential of these compounds and to characterize the myocardial pharmacokinetics in order to provide a possible explanation for differences in cardiotoxicity. Groups of rabbits received i.v. injections of drug at maximally tolerated treatment doses with respect to lymphohematopoietic toxicity for periods of 11 or 16 weeks and were evaluated histopathologically for the development of myocardial damage. Following a single i.v. administration of the different anthracyclines to rabbits, the amount of parent drug and metabolites accumulating in the heart at various times was determined by high-pressure liquid chromatography and fluorometry. Adriamycin (ADR), daunorubicin (DNR), and detorubicin produced similar severe cardiomyopathy with frequent congestive heart failure at approximately equal dose levels. Three additional antibiotics, rubidazone and the N-L-leucyl derivatives of ADR and DNR (N-L-leucyl-adriamycin and N-L-leucyl-daunorubicin), produced significantly less severe lymphohematopoietic toxicity, thus permitting the administration of 3 to 3.5 times the ADR and DNR treatment doses. Chronic treatment with these anthracyclines also resulted in significantly less cardiomyopathy, especially in the case of N-L-leucyl-daunorubicin and rubidazone. This reduced cardiomyopathy correlated with lower total myocardial drug accumulation but, more importantly, with lower amounts of DNR or ADR accumulation in the heart. These findings suggest that the degree of anthracycline myocardial toxicity may be directly related to the relative qualitative and quantitative accumulation of drug metabolites in the myocardium.

Topics: Animals; Antibiotics, Antineoplastic; Chromatography, High Pressure Liquid; Daunorubicin; Dose-Response Relationship, Drug; Doxorubicin; Female; Fluorometry; Glycosides; Heart Diseases; Heart Failure; Injections, Intravenous; Kinetics; Myocardium; Naphthacenes; Rabbits