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Sensitivity and Resistance to Therapy

Phase I study of cinchonine, a multidrug resistance reversing agent, combined with the CHVP regimen in relapsed and refractory lymphoproliferative syndromes

Leukemia volume 14, pages 2085–2094 (2000)Cite this article

Abstract

Overexpression of P-glycoprotein (P-gp) in cancer cells reduces intracellular accumulation of various anticancer drugs including anthracyclines and vinca alkaloids. This multidrug resistance (MDR) phenotype can be reversed in vitro by a number of non-cytotoxic drugs. We have identified the quinine's isomer cinchonine as a potent MDR reversing agent, both in vitroand in animal models. Here, we report an open phase I dose escalation trial in patients with refractory or relapsed malignant lymphoid diseases. Cinchonine dihydrochloride was administered by continuous i.v. infusion for 48 h and escalated over five dose levels ranging from 15 to 35 mg/kg/d. Cinchonine infusion started 24 h before i.v. doxorubicin (25 mg/m2), vinblastine (6 mg/m2), cyclophosphamide (600 mg/m2) and methylprednisolone (1 mg/kg/d) (CHVP regimen) and lasted for 24 h after chemotherapy infusion. Thirty-four patients received 87 cycles of CHVP/cinchonine. The MTD of cinchonine administered by continuous i.v. infusion was 30 mg/kg/d. Prolonged cardiac repolarization was the main dose-limiting toxicity. No ventricular arrhythmia including ‘torsade de pointes’ was observed. An MDR reversing activity was identified in the serum from every patient and correlated with cinchonine serum level. When infused at 30 mg/kg/d, cinchonine demonstrated a limited influence on doxorubicin pharmacokinetic. We conclude that i.v. infusion of cinchonine might be started 12 h before MDR-related chemotherapy infusion and requires continuous cardiac monitoring but no reduction of cytotoxic drug doses.

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Acknowledgements

The authors wish to thank Marie-Christine Verbist and Marie-Claire Pinel for their helpful participation in monitoring the study. INSERM U517 is supported by grants from ARC (grant No. 5817), the departemental comittees (Côte d'Or, Nièvre, Saône et Loire) of the Ligue Nationale Contre le Cancer, the Conseil Régional de Bourgogne and the Commission de Recherche Clinique du CHU de Dijon.

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Authors and Affiliations

  1. Clinical Hematology Unit, CHU Le Bocage, Dijon, France

    E Solary, L Mannone, D Caillot, R-O Casasnovas, H Guy, M Grandjean & B Chauffert

  2. INSERM U517, Faculty of Medicine and Pharmacy, Dijon, France

    E Solary, B Chauffert & A Wotawa

  3. Ambulatory Blood Pressure Monitoring Unit, CHU Le Bocage, Dijon, France

    D Moreau

  4. Cardiology Unit, CHU Le Bocage, Dijon, France

    J-E Wolf & F André

  5. Clinical Hematology Unit, CHU Claude Huriez, Lille, France

    P Fenaux

  6. Pharmacology Unit, Institut Claudius Regaud, Toulouse, France

    P Canal

  7. Debiopharm SA, Lausanne, Switzerland

    M Bayssas

  8. Oncodesign SA, Dijon, France

    P Genne

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Solary, E., Mannone, L., Moreau, D. et al. Phase I study of cinchonine, a multidrug resistance reversing agent, combined with the CHVP regimen in relapsed and refractory lymphoproliferative syndromes. Leukemia 14, 2085–2094 (2000). https://doi.org/10.1038/sj.leu.2401945

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