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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.

Since liposomes are slowly resorbed from serous cavities, they may constitute a valuable tool for the treatment of peritoneal carcinomatosis. We prepared mitoxantrone (MXN)-liposomes with various lipid compositions and checked their antitumoral activity on a peritoneal carcinomatosis induced by a colon cancer cell injection (1 x 10(5) C51 cells) in BALB/c mice. MXN entrapment in liposomes was rapid and stable due to its high lipophilicity. MXN carried in phosphatidylcholine: cholesterol (2:1; G-liposomes) displayed a reduced toxicity in mice compared to the free drug. When tested at a non-toxic dose (2 mg/kg), MXN entrapped in G-liposomes proved to be as efficient as the free drug. At a higher MXN dose (3 mg/kg), both G-liposomes and phosphatidylcholine:cholesterol:dipalmitoylphosphatidylethanolamine (7:2:1) liposomes, loaded with MXN, significantly increased the life span of mice compared to the free drug and six other liposome formulations. Increase in the MXN therapeutic index, when used in the liposomal form, could then merit further clinical investigations in regard to patients with malignancies confined to serous cavities.