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Article

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

Department of Drug Sciences and Center of Excellence on Aging, G. d'Annunzio University School of Medicine, Chieti, Italy (G.M., P.M., E.S.); Institute of General Pathology, University of Milan School of Medicine, Milan, Italy (G.C.); and Unit of Medical Oncology, Istituto Nazionale Tumori, Milan, Italy (L.G.)

Abstract

I. Introduction

II. Antitumor Activity of Anthracyclines

A. General Considerations

1. Anthracyclines as Topoisomerase II Poisons.

2. Anthracyclines and Apoptosis: Role of DNA Damage and p53.

B. Advances in DNA Damage by Anthracyclines

1. Role of the Proteasome.

2. Role of Free Radicals.

3. Lipid Peroxidation and DNA Damage: Malondialdehyde-DNA Adducts.

4. Oxidative Base Lesions as in Vivo Markers of Free Radical Formation and DNA Damage by Anthracyclines.

5. Anthracycline-Formaldehyde Conjugates and DNA Virtual Cross-Linking.

6. Anthracyclines and Telomeric DNA.

III. Cardiotoxicity of Anthracyclines

A. Morphology, Dose Dependence, Risk Factors

B. Mechanisms

1. Advances in Apoptosis: in Vitro Studies.

a. Doxorubicin, Iron, and Apoptosis: Role of Ferritin.

b. Doxorubicin, Iron, and Apoptosis: Role of Cytoplasmic Aconitase/Iron Regulatory Protein-1.

2. Advances in Apoptosis: in Vivo Studies.

3. Multifactorial Processes in Chronic Cardiotoxicity.

a. Pharmacokinetics of Secondary Alcohol Metabolites.

b. Iron-Dependent and -Independent Mechanisms of Toxicity by Secondary Alcohol Metabolites.

c. Unifying Mechanisms of Chronic Cardiomyopathy.

C. Enhancement by Other Agents

1. Taxanes.

2. Trastuzumab.

3. Cyclooxygenase-2 Inhibitors.

D. Prevention

1. Slow Infusion.

2. Antioxidants.

3. Iron Chelators (Dexrazoxane).

E. Treatment

IV. Toward a Better Anthracycline

A. Tumor-Targeted Formulations

1. Liposomal Formulations.

a. Polyethyleneglycol-Coated (''Pegylated'') Liposomal Doxorubicin.

b. Uncoated Citrate-Containing Liposomal Doxorubicin.

c. Liposomal Daunorubicin.

d. Immunoliposomes.

2. Extracellularly Tumor-Activated Prodrugs

3. Polymer-Bound Doxorubicin

B. Analogs

1. Nuclear-Targeted Anthracyclines.

a. Morpholinyl Anthracyclines.

b. Alkyl Anthracyclines.

c. Disaccharide Anthracyclines.

2. Non-Nuclear-Targeted Anthracyclines: 14-O-Acyl-anthracyclines.

V. Conclusions

The clinical use of anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-à-vis toxicity in cardiomyocytes) that anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index.

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