Potential usefulness of quinine to circumvent the anthracycline resistance in clinical practice

Chauffert, Bruno; Pelletier, H; Corda, C; Solary, Éric; Bedenne, Laurent; Caillot, Denis; Martin, François

doi:10.1038/bjc.1990.305

Cited by 27 publications

(12 citation statements)

References 13 publications

(13 reference statements)

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“…17,18 We have previously demonstrated that quinine was a good candidate for evaluating the clinical interest of MDR-reversing agents. 19 Serum from patients receiving conventional doses of quinine by intravenous infusion reverses the MDR phenotype of various tumor cell lines. 19,20 Quinine is safe when combined with mitoxantrone and cytarabine for treating acute leukemia patients.…”

Section: Introductionmentioning

confidence: 99%

“…19 Serum from patients receiving conventional doses of quinine by intravenous infusion reverses the MDR phenotype of various tumor cell lines. 19,20 Quinine is safe when combined with mitoxantrone and cytarabine for treating acute leukemia patients. 21,22 This compound does not significantly improve the response rate of refractory and relapsed acute myelogenous leukemias 22 but increases the response of P-glycoprotein-expressing myelodysplastic syndromes to a mitoxantrone-Ara-C combination.…”

Section: Introductionmentioning

confidence: 99%

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Quinine as a multidrug resistance inhibitor: a phase 3 multicentric randomized study in adult de novo acute myelogenous leukemia

Solary

Drénou

Campos

et al. 2003

Blood

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for the Groupe Ouest Est Leucé mies Aiguë s Myé loblastiques (GOELAMS)Based on our previous demonstration that quinine could be used clinically to reverse P-glycoprotein-mediated resistance, we designed a multicenter, randomized trial aiming to determine whether quinine would improve the survival of adult patients (15-60 years old) with de novo acute myelogenous leukemia (AML). These patients randomly received (n ‫؍‬ 213) or did not receive (n ‫؍‬ 212) a 30 mg/kg/day continuous intravenous infusion of quinine in combination with induction chemotherapy combining idarubicine and cytarabine and, depending on bone marrow examination at day 20, an additional course of cytarabine and mitoxantrone. The mean steady-state quinine concentration was 7.8 mg/L and the mean multidrug resistance reversing activity of serum was 1.96. Complete remission (CR) was obtained in 344 patients (80.9%) without significant influence of quinine. Of the patients in complete remission, 82 were assigned to receive HLA-matched bone marrow transplants, whereas 262 were assigned to 2 courses of intensive consolidation chemotherapy, with or without quinine, depending on initial randomization. The 4-year actuarial overall survival (OS) of the 425 eligible patients was 42.0% ؎ 2.5%, without significant influence of quinine. Of 160 patients who could be studied, 54 demonstrated rhodamine 123 efflux. In these patients, quinine significantly improved the CR rate from 12 of 25 (48.0%) to 24 of 29 (82.8%) (P ‫؍‬ .01). However, there was no significant difference in OS. Neither mdr1 gene nor P-glycoprotein expression influenced the outcome. We conclude that quinine does not improve the survival of adult patients with de novo AML, even though it improves CR rate in a small subgroup of patients defined by rhodamine 123 efflux.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quinine as a multidrug resistance inhibitor: a phase 3 multicentric randomized study in adult de novo acute myelogenous leukemia

Solary

Drénou

Campos

et al. 2003

Blood

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“…These agents include verapamil, 8) nifedipine, 9) quinidine, 10) quinine, 11) cyclosporin, 12) tamoxifen, 13) and toremifene. 14) Among these P-glycoprotein inhibitors of the first generation, verapamil and cyclosporin were the most active and most often tested in clinical studies.…”

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confidence: 99%

Phase I Study of Intravenous PSC‐833 and Doxorubicin: Reversal of Multidrug Resistance

Minami¹,

Ohtsu²,

Fujii³

et al. 2001

Japanese Journal of Cancer Research

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PSC-833 reverses multidrug resistance by P-glycoprotein at concentrations ≤ ≤ ≤ ≤1000 ng/ml. A phase I study of PSC-833 and doxorubicin was conducted to determine the maximum tolerated dose and to investigate pharmacokinetics. PSC-833 was intravenously infused as a 2-h loading dose (LD) and a subsequent 24-h continuous dose (CD). Doxorubicin was infused over 5 min, 1 h after the LD. The starting dose was 1 mg/kg for both LD and CD with 30 mg/m 2 doxorubicin; these dosages were increased to 2 and 10 mg/kg and 50 mg/m 2 , respectively. Thirty-one patients were treated. Nausea/ vomiting was controllable with granisetron and dexamethasone. Neutropenia and ataxia were dose limiting. Steady-state concentrations of PSC-833 > > > >1000 ng/ml were achieved at a 2 mg/kg LD and a 10 mg/kg CD. Ex-vivo bioassay revealed that activity in serum for reversing multidrug resistance was achieved in all patients; IC 50 of P-glycoprotein expressing 8226/Dox 6 in patients' serum was decreased from 5.9 to 1.3 µ µ µ µg/ml (P < < < <0.0001) by PSC-833 administration. Doxorubicin clearance was 24.3 ± ± ± ±13.7 (mean ± ± ± ±SD) liter/h/m 2 , which was lower than the 49.0 ± ± ± ±16.9 liter/h/m 2 without PSC-833 (P < < < <0.0001). The relationship between doxorubicin exposure and neutropenia did not differ between patients treated and not treated with PSC-833. The recommended phase II dose of PSC-833 was 2 and 10 mg/kg for LD and CD, respectively, which achieved a sufficient concentration in serum to reverse drug resistance, as confirmed by bioassay. The dose of doxorubicin should be reduced to 40 mg/m 2 , not because of the pharmacodynamic interaction between PSC-833 and doxorubicin affecting hematopoiesis, but because of pharmacokinetic interaction.

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“…17 The clinical use of most of these drugs is precluded by serum protein binding or clinical toxicity. 18 We observed that serum from patients receiving conventional doses of quinine by intravenous infusion reversed the MDR phenotype of rat colon cancer 19 and human leukemic cells. 20 Based on this observation, quinine appeared as a good candidate for evaluating the clinical interest of MDR reversing agents.…”

Section: Introductionmentioning

confidence: 90%

“…[17][18][19] A 12-h cinchonine infusion was required to reach an optimal MRA. After cinchonine infusion arrest, both drug serum level and MRA decreased rapidly, suggesting that cinchonine infusion might be maintained for at least 3 h after chemotherapeutic drug administration.…”

Section: Discussionmentioning

confidence: 99%

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

Solary

Mannone²,

Moreau³

et al. 2000

Leukemia

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Potential usefulness of quinine to circumvent the anthracycline resistance in clinical practice

Cited by 27 publications

References 13 publications

Quinine as a multidrug resistance inhibitor: a phase 3 multicentric randomized study in adult de novo acute myelogenous leukemia

Quinine as a multidrug resistance inhibitor: a phase 3 multicentric randomized study in adult de novo acute myelogenous leukemia

Phase I Study of Intravenous PSC‐833 and Doxorubicin: Reversal of Multidrug Resistance

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

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