Comparative cardiotoxicity and antitumour activity of doxorubicin (adriamycin) and 4'-deoxydoxorubicin and the relationship to in vivo disposition and metabolism in the target tissues.

4'-Deoxydoxorubicin (4'-DOX) is an analogue of the anticancer drug Adriamycin (ADR) believed to lack its cardiotoxicity. Bioreduction to a semi-quinone free radical has been implicated in the etiology of ADR induced cardiotoxicity. We have studied (in a rat model) acute cardiotoxicity (after 16 mg/kg i.v. of both drugs), antitumour activity (after 5 mg/kg i.v.) and the relationship to disposition and metabolism in the target tissues (after 5 mg/kg i.v.). 7-Deoxyaglycones, which are considered inactive lipophilic metabolites derived from ADR semi-quinone, were utilised as markers of in vivo tissue free radical generation. Both drugs produced toxicity of equal severity to hearts after 24 hr, associated with high cardiac levels of 7-deoxyaglycones in the case of ADR (AUC0-48 hr, micrograms/g X hr: ADR, 47; ADR 7-deoxyaglycone (ADR-DONE), 24; and adriamycinol 7-deoxyaglycone (AOL-DONE), 35) compared to low cardiac levels of 7-deoxyaglycones but a times five higher peak cardiac concentration of parent drug in the case of 4'-DOX (AUC0-48 hr, micrograms/g X hr: 4'-DOX, 68; 4'-DOX-DONE, 3.8; and 4'-DOL-DONE, 0.8). 4'-DOX displayed superior antitumour activity to ADR against the MC 40A sarcoma growing sub-cutaneously, achieving higher concentrations of parent drug in tumour (AUC0-48 hr, micrograms/g X hr: 4'-DOX, 150; ADR, 60). There was an absence of 7-deoxyaglycones of both drugs in the tumour. These data suggest that drug bioreduction is involved principally only in ADR induced cardiotoxicity and that the level of unchanged parent drug achieved in the tumour is the most important pharmacokinetic determinant of antitumour activity for both ADR and 4'-DOX.