Comparative effects of quinine and cinchonine in reversing multidrug resistance on human leukemic cell line K562/ADM.
We have previously suggested that quinine and cinchonine could be good candidates for clinical circumvention of multidrug resistance (MDR) in hematological malignancies because of their tolerance and their retained efficacy in serum. In the present study, we have used the well-characterized multidrug resistant human leukemic cell line K562/ADM to compare the effect in vitro of quinine and cinchonine on doxorubicin, mitoxantrone, and vincristine uptake and cytotoxicity. In serum-free medium, quinine induced a dose-dependent increase of doxorubicin uptake reaching about 200% at 40 microM, while it had a slight and no effect on mitoxantrone and vincristine uptake respectively. In the same conditions, cinchonine induced a rapid and significant increase in the accumulation of the three drugs, reaching a plateau phase between 5 and 10 microM. Quinine and cinchonine induced both potentiation of doxorubicin, vincristine and mitoxantrone cytotoxicity in K562/ADM cells. However, quinine reached a plateau phase at 10 microM, while cinchonine had a maximal effect at 5 microM and was significantly more potent at low concentrations. When diluted in plasma, cinchonine was less bound to proteins than quinine. The free fraction of alkaloids was 37-55% for cinchonine and 20-30% for quinine. Cinchonine-induced enhancement of vincristine cellular accumulation was little modified by plasma proteins. When incubated in whole blood, the fraction of cinchonine trapped in red blood cells was rapidly and completely exchangeable with plasma. We conclude that cinchonine is a stronger inhibitor of MDR than quinine.
Genne
P
P
INSERM U252, Faculty of Medecine, Dijon, France.
Duchamp
O
O
Solary
E
E
Pinard
D
D
Belon
J P
JP
Dimanche-Boitrel
M T
MT
Chauffert
B
B
D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001798:Blood Proteins / Q000378:metabolism; D002930:Cinchona Alkaloids / Q000097:blood / Q000494:pharmacology*; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D004351:Drug Resistance / Q000235:genetics; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D008942:Mitoxantrone / Q000493:pharmacokinetics / Q000494:pharmacology; D011803:Quinine / Q000097:blood / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014750:Vincristine / Q000493:pharmacokinetics / Q000494:pharmacology
D000970:Antineoplastic Agents; D001798:Blood Proteins; D002930:Cinchona Alkaloids; D014750:Vincristine; D004317:Doxorubicin; D011803:Quinine; D008942:Mitoxantrone; C010086:cinchonine