Correlation between tumour drug disposition and the antitumour activity of doxorubicin-loaded microspheres: implications for the drugs' in vivo mechanism of action.
Doxorubicin (DOX) has been incorporated into five different formulations of protein microspheres, each altering tumour drug disposition in a characteristic manner. There was no correlation between the stimulation in anaerobic quinone bioreduction over the levels produced by free DOX and tumour growth delay against the Sp 107 rat mammary carcinoma. A strong correlation (r2 = 0.948, P < 0.01, two-tailed t statistic) was observed between a slower decline in parent drug levels and antitumour activity. These data support the view that free radical processes are not involved in the mechanism of action of DOX and suggest that the optimum way to delivery the drug to the Sp 107 tumour is through sustained release of lower concentrations (approximately 2 microM) from a large extracellular pool.
Cummings
J
J
Imperial Cancer Research Fund, Medical Oncology Unit, Western General Hospital, Edinburgh, U.K.
Willmott
N
N
Marley
E C
EC
Smyth
J F
JF
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D005976:Glutaral / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008863:Microspheres; D011506:Proteins / Q000378:metabolism; D051381:Rats
D003692:Delayed-Action Preparations; D011506:Proteins; D004317:Doxorubicin; D005976:Glutaral