Abstract
Cardiotoxicity and acquired drug resistance of tumor cells have been two impediments for the clinical use of doxorubicin (DOX). Trials are ongoing using buthionine sulfoximine (BSO) to deplete glutathione (GSH) content in tumors, whose elevation was found to contribute to the acquired drug resistance. However, BSO also decreases GSH content in the heart, enhancing DOX cardiotoxicity. Recent studies have shown that metallothionein (MT) is an important factor in cardiac protection against DOX. Our study was undertaken to determine whether MT can compensate for the loss of protection from GSH depletion in the heart. Transgenic mice with cardiac MT concentrations about 20-fold higher than normal, and nontransgenic controls were treated with BSO by i.p. injection at 5 mmol/kg, two times with a 12-hr interval, before treatment with DOX at a single dose of 15 mg/kg, lasting for 4 days. Cardiac GSH was depleted by 60% in both transgenic and non-transgenic mice. DOXinduced cardiotoxicity, as measured by blood levels of creatine kinase and malondialdehyde concentrations in the heart, was dramatically increased in the BSO-treated nontransgenic mice. This increase was completely inhibited in the BSO-treated transgenic mice. These results demonstrate that cardiac MT overexpressing transgenic mice are resistant to BSO-enhanced DOX cardiotoxicity. Selective modulations of decreasing DOX resistance in tumors by BSO and of increasing cardioprotection by MT induction may provide an alternative approach to improved DOX chemotherapeutic efficacy.
Footnotes
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Send reprint requests to: Dr. Y. James Kang, Department of Medicine, University of Louisville School of Medicine, 530 S. Jackson St., Louisville, KY 40202.
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↵1 This work was supported in part by a National Institutes of Health Grants CA68125 and an EI Award from the American Heart Association #9640091N (to Y.J.K.). Y.J.K. is a University scholar of the University of Louisville. This work was presented in part at the Fourth International Metallothionein Meeting held in Kansas City, MO, September 17–20, 1997.
- Abbreviations:
- CK
- creatine kinase
- DOX
- doxorubicin
- GSH
- glutathione
- GSSG
- glutathione disulfide
- GSHpx
- glutathione peroxidase
- GR
- glutathione reductase
- γ-GCS
- γ-glutamylcysteine synthetase
- MDA
- malondialdehyde
- MT
- metallothionein
- BSO
- buthionine sulfoximine
- DTNB
- 5,5′-dithiobis(2-nitrobenzoic acid
- HPLC
- high-performance liquid chromatography
- Received April 7, 1998.
- Accepted June 13, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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