Reducing the cardiotoxicity of anthracyclines by complex-bindin to DNA

Abstract

Three patients with acute myeloblastic leukemia received high doses of daunorubicin, first in the free form and later as complex with DNA. Two of the patients also received doxorubicin-DNA. Two patients showed symptoms of cardiotoxicity with signs of congestive heart failure after cumulative doses of 910 and 250 mg of noncomplexed daunorubicin/m2 body surface area, respectively. Thereafter they tolerated daunorubicin-DNA complex up to total doses of 1430 mg and 1200 mg daunorubicin/m2, respectively, with no further signs of cardiotoxicity. One of them entered another complete remission after therapy with the complex. The third patient had received 820 mg daunorubicin/m2 and was in his second relapse when he was switched to daunorubicin-DNA complex. A new remission was induced and the patient received a total daunorubicin dose of 1480 mg/m2 with no clinical signs of cardiotoxicity. However, a cardiac biopsy showed minor myocardial changes, which could have been due to daunorubicin. During a third relapse the patient received 270 mg/m2 doxorubicin-DNA. At autopsy still only minor signs of cardiomyopathy were seen. Thus, complex-binding of anthracyclines with the DNA appears to enhance the usefulness of these drugs in the treatment of patients with leukemia.

Compartmentalization of adriamycin and daunomycin in cultured chick cardiac myocytes. Effects on synthesis of contractile and cytoplasmic proteins.

“…Evidence exists concerning the interaction of ADR with cardiac cell membranes (Duarte-Karim et al, 1976;Caroni et al, 1981), and its binding affinity for selected cytoskeletal and contractile proteins (Lewis et al, 1982;Someya et al, 1978;Na and Timasheff, 1977) and nucleic acids (Paul et al, 1981;Trouet and DePrez-Decampaneere, 1979). However, the binding sites of ADR, and its uptake pathways, subcellular compartmentalization, and ultimate metabolic fate have not been completely elu-cidated for heart cells (Skovsgaard, 1978;Dano, 1976).…”