Preclinical toxicity of liposome-incorporated annamycin: selective bone marrow toxicity with lack of cardiotoxicity.
Annamycin (Ann) is a new lipophilic anthracycline antibiotic with a marked ability to circumvent typical multidrug resistance both in vitro and in vivo. Because of its high affinity for lipid membranes and very low solubility in water, Ann has been prepared in a submicron liposome formulation (L-Ann) that is currently being investigated in a Phase I clinical study. We studied the preclinical toxicity of L-Ann in mice and beagle dogs and compared it with that of free Ann in suspension and the parent compound doxorubicin (Dox). In mice, free Ann was about twice as toxic as Dox (LD50 after a single i.v. bolus administration, 8.8 versus 19.9 mg/kg; P < 0.01). The liposomal carrier reduced Ann toxicity by 2-fold (LD50, 15.74 mg/kg for L-Ann versus 8.8 mg/kg for free Ann; P < 0.01). Granulocytopenia was the main toxicity of Ann, either free or liposome incorporated, and was much more profound than with an equitoxic dose of Dox as assessed by blood counts and pathological studies. In chronic mouse studies, L-Ann was remarkably less cardiotoxic than Dox. Cumulative toxicity with the weekly administration of a given fraction of the subacute LD10 was markedly higher with Dox than with L-Ann as assessed by body weight and mortality studies. L-Ann also had less vesicant toxicity than Dox after intradermal administration in mice. Beagle dogs tolerated the mouse-equivalent LD10 dose of L-Ann (1.4 mg/kg) with no side effects, changes in the hematological and biochemical blood parameters, or pathological changes. Our results indicate that: (a) L-Ann is more selectively myelotoxic than Dox and is noncardiotoxic; (b) the liposome carrier plays a major role in the favorable toxicity profile of L-Ann; and (c) the standard one-tenth of the LD10 should be a safe starting dose for Phase I clinical trials with L-Ann in humans.
Zou
Y
Y
Section of Experimental Therapy, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030,
Priebe
W
W
Stephens
L C
LC
Perez-Soler
R
R
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000097:blood / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects*; D004285:Dogs; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000097:blood / Q000633:toxicity; D004337:Drug Carriers; D004354:Drug Screening Assays, Antitumor; D006098:Granulocytes / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D007928:Lethal Dose 50; D007958:Leukocyte Count / Q000187:drug effects; D008081:Liposomes; D008297:Male; D051379:Mice; D012867:Skin / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008081:Liposomes; D004317:Doxorubicin; C080315:annamycin