Musettamycin

The metabolism and tissue distribution of aclacinomycin A (ACL), marcellomycin (MCM), and musettamycin (MST), three new anthracycline antibiotics, were compared after IV administration to mice. In plasma, total MCM- and ACL-derived fluorescence declined according to first-order kinetics, whereas an initial decline followed by a rebound was observed for MST. In plasma, MCM remained the predominant compound. ACL was eliminated more quickly, and was replaced by two metabolites, the reduced glycoside M1, and an aglycone. In the case of MST, two unidentified metabolites were observed in concentrations equivalent to that of the parent drug. The three drugs were distributed widely to organs, but only ACL achieved measurable concentrations in the brain. Initially, high concentrations of all three drugs were present in the lungs, but these decreased quickly to values similar to those present in the liver and kidneys. Intermediate concentrations of the three drugs were measured in heart and skeletal muscle. Splenic concentrations of all three drugs rose progressively, reaching a maximum at 8 h after injection in the case of ACL and MST, and at 24 h after injection in the case of MCM. Concentrations of the metabolites of MCM and MST were low in all organs except liver and kidney, where the aglycones 7-deoxypyrromycinone and bisanhydropyrromycinone were seen. The metabolism of ACL was extensive. Aglycones were dominant in the liver and kidneys, whereas reduced glycosides predominated in the spleen. These observations indicate that the murine pharmacology of these three structurally similar drugs differs markedly.

The oligosaccharide-anthracyclines, aclacinomycin A, marcellomycin and musettamycin, are potent inducers of erythroid differentiation in hemopoietic cells lines of rodent and human origin. The present studies revealed that pyrromycin, a closely related monosaccharide-anthracycline, induced erythroid differentiation in Friend leukemia cells and in the human leukemia cell line K 562. Pyrromycin, marcellomycin and musettamycin, which possess an identical aglycone structure containing a Cl-hydroxyl group, exhibited relatively low optimal inductive concentrations. In contrast, the optimal inductive concentration of aclacinomycin A, which lacks the Cl-hydroxyl group, was markedly higher, i.e., the differentiation inducing capacity was lower. It should be noted, however, that the yield of differentiated cells following treatment with the monosaccharide-anthracycline pyrromycin was distinctly lower than that after treatment with the oligo-saccharide-anthracyclines, aclacinomycin A, marcellomycin or musettamycin. Thus, our data indicate that the efficacy of anthracyclines to induce erythroid differentiation is related to a) the presence of a Cl-hydroxyl group in the aglycone and b) the presence of an oligosaccharide side chain.

The oligosaccharide anthracycline aclacinomycin A is of considerable clinical interest since, in comparison to adriamycin and daunomycin, the compound exhibits reduced cardiac toxicity and is devoid of mutagenicity/carcinogenicity. In addition, induction of differentiation in the human promyelocytic leukemia cell line HL 60 and possibly in one case of human acute myeloblastic leukemia by aclacinomycin A has been observed. Our data indicate that aclacinomycin A and related compounds, such as musettamycin and marcellomycin, are extremely potent inducers of differentiation in mouse (Friend leukemia cells, clone F4-6), rat (rat erythroleukemia, clone D5A1), and human erythroid cell lines (K 562 cell line) and that the relative inductive potency of marcellomycin and musettamycin, in general, is higher than that of aclacinomycin A. This potency difference may be due to the presence of a Cl-hydroxyl group in the aglycone of the marcellomycin and musettamycin molecule. Thus, oligosaccharide anthracyclines are a new class of inducers of erythroid differentiation. The high potency of these compounds, the possibility to study structure-activity relationships relative to their inductive potency and the fact that they induce erythroid differentiation in cells of different species as well as granulocytic differentiation in human cells should facilitate the study of basic mechanisms of hemopoietic differentiation. In addition, the therapeutical significance of these anthracycline effects should be investigated by studying, comparatively, the differentiation-inducing and antitumor effects of these compounds in primary leukemic cell cultures from patients.