Effects of ibuprofen on doxorubicin toxicity.
The cardiotoxicity of doxorubicin (Adriamycin) restricts the usefulness of this potent antineoplastic agent. Since the cardiotoxic mechanism (generation of oxygen radicals) is distinct from the primary chemotherapeutic mechanism (intercalation of DNA) efforts to decrease the cardiotoxic potential are warranted. Three nonsteroidal anti-inflammatory drugs, aspirin, ibuprofen and sulindac were tested for effects upon survival in the chronic mouse model of doxorubicin cardiotoxicity. The original premise in these studies was that nonsteroidal anti-inflammatory drugs, through inhibition of cyclooxygenase activity, would suppress the attending generation of superoxide anions and reduce a synergism with oxygen radicals produced by redox cycling of doxorubicin. Acetaminophen was included in the studies as an example of an analgesic agent which lacks anti-inflammatory efficacy. Doxorubicin (4 mg/kg) was injected intraperitoneally at 3-week intervals in Swiss-Webster mice. The interventions were administered in equianalgesic doses in the drinking water for 2 days before and 3 days after the doxorubicin injections. Ibuprofen (1 mg/ml) increased survival from 16.0%, for doxorubicin alone, to 63.6% (p less than 10(-6); none of the other interventions demonstrated protection. Ibuprofen-treated mice also lost less weight during the treatment period than all other doxorubicin injected animals (p less than 10(-6]. Since the three antiinflammatory drugs tested are all cyclooxygenase inhibitors, but only ibuprofen inhibits neutrophil infiltration, the latter mechanism is proposed as the primary basis for the observed protection.
Inchiosa
M A
MA
Department of Pharmacology, New York Medical College, Valhalla 10595.
Smith
C M
CM
D000082:Acetaminophen / Q000494:pharmacology; D000205:Actomyosin / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D006331:Heart Diseases / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control; D007052:Ibuprofen / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D009206:Myocardium / Q000201:enzymology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000082:Acetaminophen; D004317:Doxorubicin; D000205:Actomyosin; D000251:Adenosine Triphosphatases; D007052:Ibuprofen