Preclinical toxicity of liposome-incorporated annamycin: Selective bone marrow toxicity with lack of cardiotoxicity

Yiyu Zou, W. Priebe, L. C. Stephens, Roman Perez-Soler

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1369-1374
Number of pages6
JournalClinical Cancer Research
Volume1
Issue number11
StatePublished - 1995
Externally publishedYes

Fingerprint

Liposomes
Bone Marrow
Doxorubicin
annamycin
Cardiotoxicity
Lethal Dose 50
Dogs
Clinical Trials, Phase I
Agranulocytosis
Irritants
Poisons
Anthracyclines
Multiple Drug Resistance
Membrane Lipids
Solubility
Suspensions

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Preclinical toxicity of liposome-incorporated annamycin : Selective bone marrow toxicity with lack of cardiotoxicity. / Zou, Yiyu; Priebe, W.; Stephens, L. C.; Perez-Soler, Roman.

In: Clinical Cancer Research, Vol. 1, No. 11, 1995, p. 1369-1374.

Research output: Contribution to journalArticle

@article{b2596cd31149446e959185504b5be1e5,
title = "Preclinical toxicity of liposome-incorporated annamycin: Selective bone marrow toxicity with lack of cardiotoxicity",
abstract = "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.",
author = "Yiyu Zou and W. Priebe and Stephens, {L. C.} and Roman Perez-Soler",
year = "1995",
language = "English (US)",
volume = "1",
pages = "1369--1374",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "11",

}

TY - JOUR

T1 - Preclinical toxicity of liposome-incorporated annamycin

T2 - Selective bone marrow toxicity with lack of cardiotoxicity

AU - Zou, Yiyu

AU - Priebe, W.

AU - Stephens, L. C.

AU - Perez-Soler, Roman

PY - 1995

Y1 - 1995

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0028880010&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028880010&partnerID=8YFLogxK

M3 - Article

C2 - 9815933

AN - SCOPUS:0028880010

VL - 1

SP - 1369

EP - 1374

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 11

ER -