Cinchonine, a potent efflux inhibitor to circumvent anthracycline resistance in vivo.
Circumvention of multidrug resistance is a new field of investigation in cancer chemotherapy, and safe and potent multidrug resistance inhibitors are needed for clinical use. We investigated several analogues of quinine for their ability to increase anthracycline uptake in resistant cancer cells. Cinchonine was the most potent inhibitor of anthracycline resistance in vitro, and its activity was little altered by serum proteins. Serum from rats treated with i.v. cinchonine produced greater uptake of doxorubicin in cancer cells (DHD/K12/PROb rat colon cells and K562/ADM human leukemic cells) than did serum from quinine-treated rats (ex vivo assay). Cinchonine was more effective than quinine in reducing tumor mass and increasing the survival of rats inoculated i.p. with DHD/K12/PROb cells and treated i.p. with deoxydoxorubicin. Moreover, the acute toxicity of cinchonine in rats and mice was lower than that of other quinine-related compounds. The lower toxicity and greater potentiation of in vivo anthracycline activity produced by cinchonine are favorable characteristics for its use as an anti-multidrug resistance agent in future clinical trials.
Genne
P
P
Research Group on Digestive Tumors, INSERM U.252, Faculty of Medicine, University of Dijon, France.
Dimanche-Boitrel
M T
MT
Mauvernay
R Y
RY
Gutierrez
G
G
Duchamp
O
O
Petit
J M
JM
Martin
F
F
Chauffert
B
B
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D002930:Cinchona Alkaloids / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D004357:Drug Synergism; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011803:Quinine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D002930:Cinchona Alkaloids; D004317:Doxorubicin; D011803:Quinine; C030851:esorubicin; C010086:cinchonine