Biological Activity and Therapeutic Usefulness of Daunomycin

Abstract

Daunomycin is a new antibiotic of the anthracycline group obtained from Streptomyces peucetius; it consists of a pigmented aglycone (daunomycinone) in glycoside linkage with an aminosugar (daunosamine), Strictly related substances are Rubidomicine and Rubomycin C. Daunomycin has a strong cytotoxic and antimitotic effect on the «in vitro» growth of mammalian normal and neoplastic cells. Its most important metabolic effect is the inhibition of the synthesis of RNA and DNA. This effect can be considered as a result of the binding of Daunomycin to DNA. The antimitotic activity of Daunomycin however is only in part dependent on this metabolic effect. Daunomycin has a strong inhibiting effect on the growth of transplanted tumors, both in the ascitic and solid forms with a remarkable prolongation of survival time in animals. In experimental leukemia this antibiotic shows a significant therapeutic effect also on advanced systemic L 1210, on the leukemia transplantable linea resistant to methotrexate, 6MP, and cyclophosphamide. The most pronounced toxic effects of Daunomycin are bone marrow depression and marked reduction in lymphoid tissues; histological studies in the lethal dose range showed also degenerative changes in liver, kidney, intestinal tract and testis. Daunomycin is not effective by mouth probably because it is inactivated in the gastro-intestinal tract; in fact the antibiotic is quickly transformed by liver extracts in inactive products. The observed toxic effects in man are: severe local reactions if the drug extravasates, bone marrow depression, leucopenia, anemia, thrombocytopenia, bleeding, fever, oral ulcers and alopecia. Liver disturbances were observed in some patients treated with Daunomycin. In patients receiving a total dosage of Daunomycin of 25 mg/or more, cardiac symptoms were observed, such as tachycardia, pulmonary insufficiency, heart failure and hypotension, possibly associated with the drug. Similar and more frequent effects were observed in patients treated with Rubidomicine. A relatively high remission rate was observed in acute lymphoid leukemia; the remission could be prolonged by maintenance therapy. Daunomycin was also temporarily effective in some cases of neuroblastoma, reticular cell sarcoma and rhabdomyosarcoma. A more extensive evaluation of this drug, on different neoplasias is under way at several hospitals.