Abstract |
Cardiotoxicity represents the major side-effect limiting the clinical use of anthracyclines, especially doxorubicin, in cancer chemotherapy. The use of non-toxic prodrugs, or of liposome-encapsulated drugs, allows a better targeting of the tumours and may, therefore, improve the tolerance to the treatment. Using the model of isolated perfused rat heart, we have evaluated the cardiotoxicity of a novel prodrug of doxorubicin, HMR-1826, which consists of the association of doxorubicin to glucuronic acid. We have compared the cardiac effects (developed pressure, contractility and relaxation of the left ventricle) induced by HMR-1826 to those induced by doxorubicin and Doxil, a liposomal form of doxorubicin. HMR-1826 was administered intravenously every other day for 11 days at doses of 50-200 mg kg(-1) per injection while doxorubicin was administered according to the same protocol at doses of 1-3 mg kg(-1) per injection. Doxorubicin strongly decreased the cardiac functional parameters at the doses of 2.5 and 3 mg kg(-1) per injection. Doxil (3 mg kg(-1) and HMR-1826 (50-150 mg kg(-1)) were largely devoid of cardiotoxicity. HMR-1826 only induced significant alterations of the cardiac function at the highest dose used (200 mg kg(-1) per injection). These alterations were much lower than those of doxorubicin at 2.5 mg kg(-1) per injection, despite similar general toxicity symptoms ( weight loss, nose bleeding and diarrhoea) at these respective doses. Thus, HMR-1826 appeared about 100-fold less cardiotoxic than doxorubicin.
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Authors | D Platel, S Bonoron-Adèle, R K Dix, J Robert |
Journal | British journal of cancer
(Br J Cancer)
Vol. 81
Issue 1
Pg. 24-7
(Sep 1999)
ISSN: 0007-0920 [Print] England |
PMID | 10487608
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Glucuronates
- N-(4-glucuronyl-3-nitrobenzyloxycarbonyl)doxorubicin
- Prodrugs
- Doxorubicin
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Topics |
- Animals
- Antineoplastic Agents
(pharmacokinetics, toxicity)
- Body Weight
(drug effects)
- Dose-Response Relationship, Drug
- Doxorubicin
(analogs & derivatives, pharmacokinetics, toxicity)
- Drug Evaluation, Preclinical
(methods)
- Glucuronates
(pharmacokinetics, toxicity)
- Heart Diseases
(chemically induced, prevention & control)
- In Vitro Techniques
- Male
- Myocardial Contraction
(drug effects)
- Myocardium
(metabolism)
- Prodrugs
(pharmacokinetics, toxicity)
- Rats
- Rats, Sprague-Dawley
- Ventricular Dysfunction, Left
(chemically induced)
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