Reversal of resistance to vincristine in P388 leukemia by various polycyclic clinical drugs, with a special emphasis on quinacrine.
We investigated several lipophilic drugs with a polycyclic structure for their effect on the net uptake of vincristine in vincristine-resistant P388 leukemia cells. Fourteen of 23 agents promoted vincristine uptake in the resistant cells. The net increase in vincristine uptake was caused by prevention of its outward transport rather than by stimulation of inward transport. Some of these drugs, e.g., quinacrine, dilazep, syrosingopine, simetride, etc., remarkably potentiated the cytotoxicity of vincristine against the resistant cells in vitro. Quinacrine, an antimalarial drug which had the greatest effect on vincristine uptake and relatively low host toxicity, exhibited potent therapeutic synergism in combination with vincristine in resistant leukemia-bearing mice.
Inaba
M
M
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Maruyama
E
E
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004357:Drug Synergism; D007941:Leukemia P388 / Q000188:drug therapy* / Q000378:metabolism; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D011796:Quinacrine / Q000008:administration & dosage / Q000494:pharmacology*; D014750:Vincristine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
D014750:Vincristine; D004317:Doxorubicin; D011796:Quinacrine