epicinchonine and Colonic-Neoplasms

We have previously suggested that quinine and cinchonine could be good candidates for the clinical circumvention of multidrug resistance (MDR) in haematological malignancies because of their tolerance and their retained efficacy in serum. We have also shown that cinchonine was more efficient than quinine as an anti-MDR agent in vitro, ex vivo and in vivo after parenteral administration. Here, we report that cinchonine administered per os (po) is much more active than quinine po in circumventing MDR in rats bearing resistant colon tumours. The pharmacokinetics of cinchonine and quinine administered po in rat are shown to be very different. Cinchonine demonstrates a greater absolute bioavailability than quinine (44% versus 30%, respectively). Its serum concentration correlates with the anti-MDR activity measured ex vivo and in vivo. Cinchonine administered po does not significantly modify the pharmacokinetics of intravenous doxorubicin (DXR). However, cinchonine induces a significant increase of DXR uptake in organs which express the mdr1 gene (liver, kidney, lung). When associated with VAD (vincristine, adriamycin, dexamethasone) combined therapy in rats, cinchonine does not significantly increase the toxicity of the cytotoxic drugs. Based on these experimental data, a phase I clinical trial is currently in progress to test the tolerance of this potent MDR-reversing agent administered po.

Topics: Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Cinchona Alkaloids; Colonic Neoplasms; Dexamethasone; Doxorubicin; Drug Resistance, Multiple; Drug Synergism; Female; Infusions, Intravenous; Quinones; Rats; Tissue Distribution; Tumor Cells, Cultured; Vincristine

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.

Topics: Animals; Antibiotics, Antineoplastic; Cinchona Alkaloids; Colonic Neoplasms; Doxorubicin; Drug Resistance, Microbial; Drug Synergism; Female; Male; Mice; Mice, Inbred BALB C; Quinine; Rats; Rats, Inbred Strains; Tumor Cells, Cultured