Cardiac resistance to adriamycin in transgenic mice expressing a rat alpha-cardiac myosin heavy chain/human multiple drug resistance 1 fusion gene.
Cardiac toxicity is a major factor that limits the use of anthracyclines in cancer chemotherapy. Heart failure frequently develops in patients treated with doxorubicin (Adriamycin), when they receive a cumulative dose greater than 500 mg/m2. To make a mouse model for gene therapy designed to prevent this toxic effect, we have produced transgenic mice overexpressing the human cDNA for the multiple drug resistance (h-mdr1) gene driven by 2.12 kb of the 5' flanking region of the rat alpha-cardiac myosin (aCM) heavy chain gene. Two lines of transgenic mice expressed the transgene at a high level in heart muscle. Transgenic and control animals were treated with Adriamycin intravenously at either a single dose of 10 mg/kg or a cumulative dose of 30 mg/kg in three injections. Subsequent light and electron microscopic examination of heart tissue demonstrated degenerative changes in control mice that were absent in transgenic animals at both doses. These results show that expression of the alphaCM/h-mdr1 transgene in heart confers protection from the toxic effect of Adriamycin and suggest that such constructs, if employed effectively in cardiac gene therapy protocols, could allow a more aggressive use of anthracyclines in the treatment of cancer.
Dell'Acqua
G
G
Department of Obstetrics/Gynecology and Reproductive Science, Mt. Sinai School of Medicine, New York, NY 10029, USA.
Polishchuck
R
R
Fallon
J T
JT
Gordon
J W
JW
D016475:3T3 Cells; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D019677:Artificial Gene Fusion; D004317:Doxorubicin / Q000494:pharmacology* / Q000633:toxicity; D004351:Drug Resistance; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018995:Myosin Heavy Chains / Q000235:genetics / Q000502:physiology*; D051381:Rats; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004317:Doxorubicin; D018995:Myosin Heavy Chains