Modulation of doxorubicin efficacy in P388 leukemia following co-administration of verapamil in mini-osmotic pumps.
Co-administration of doxorubicin and verapamil in Alzet mini-osmotic pumps increased the survival of B6D2F1 mice bearing the multidrug-resistant P388/ADR leukemia. A range of doxorubicin and verapamil combinations was studied to define dose-dependent efficacy and toxicity. High doses of doxorubicin (10 mg/kg/day) and verapamil (150 mg/kg/day) could be administered alone without any effect on survival. However, combining high doses of these two agents resulted in host toxicity. Doxorubicin doses of 1 to 10 mg/kg/day in combination with verapamil at 25-100 mg/kg/day were found to improve survival compared with either agent alone. Combination therapy also improved the survival of mice bearing the drug-sensitive P388/0 leukemia when compared to anthracycline treatment alone. The efficacy of the mini-osmotic pump delivery protocol was compared with other regimens delivering the same total cumulative dose of doxorubicin via repeated i.p. injections.
Slate
D L
DL
Institute of Biochemistry and Cell Biology, Syntex Discovery Research, Palo Alto, CA 94304.
Fraser-Smith
E B
EB
Rosete
J D
JD
Freitas
V R
VR
Kim
Y N
YN
Casey
S M
SM
D000818:Animals; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use*; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D007263:Infusions, Parenteral; D007274:Injections, Intraperitoneal; D007941:Leukemia P388 / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D014700:Verapamil / Q000008:administration & dosage / Q000627:therapeutic use*
D004317:Doxorubicin; D014700:Verapamil