Mitoxantrone, Etoposide and Cyclosporine A Therapy for Relapsed and Refractory Acute Myelogenous Leukemia, A Pediatric Oncology Group Phase II Trial

  • G. V. Dahl
  • N. Brophy
  • H. Grier
  • H. Weinstein
  • B. Sikic
  • R. Arceci
Conference paper
Part of the Haematology and Blood Transfusion / Hämatologie und Bluttransfusion book series (HAEMATOLOGY, volume 37)

Abstract

Multidrug resistance remains a major obstacle to effective treatment of patients with Acute Myelogenous Leukemia (AML). A growing body of evidence indicates that over-expression of the MDR1 gene, which encodes the multidrug transporter P-glycoprotein(P-gp), contributes to the resistance of human cancers to many anti-cancer drugs [1,2]. One strategy currently being explored to overcome this resistance is the coadministration of non-cytotoxic drugs that bind to and inhibit the function of P-gp, thereby rendering the cells sensitive to concurrently administered chemotherapy. The Pediatric Oncology Group Phase II clinical trial reported here was designed to test the safety and efficacy of this strategy. Among the agents that are currently approved for clinical trials, Cyclosporine A (CSA) is the most potent inhibitor of P-gp. CSA has been shown to reverse chemotherapeutic resistance due to expression of the MDR1 P-gp both in vitro and in animal models. Phase I trials have demonstrated that blood levels of CSA similar to those required to modulate MDR in vitro can be achieved with acceptable toxicity. Alterations in the pharmacokinetics of MDR related drugs have been reported so that chemotherapy doses need to be chosen carefully to prevent undue toxicity [5].

Keywords

Toxicity Leukemia Oncol Doxorubicin Resis 

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References

  1. 1.
    Fojo AT, Veda K., Slamon DJ., Poplack DG, Gottesmann MM and Pastan I: Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl. Acad. Sci. USA, 84: 265–269, 1987PubMedCrossRefGoogle Scholar
  2. 2.
    Pastan I and Gottesman MM. Multi-drug resistance in human cancer. N. Engl. J. Med, 316: 1388–93, 1987PubMedCrossRefGoogle Scholar
  3. 3.
    Slater LM, Sweet P, Stupecky M, and Gupta S: Cyclosporine A reverses vincristine and daunorubicin resistance in acute lymphatic leukemia in vitro. J. Clin. Investig. 77: 1405–1408, 1986PubMedCrossRefGoogle Scholar
  4. 4.
    Marie JP, Zittoun R, and Sikic BI: Multidrug resistance (mdr1) gene expression in adult acute leukemias: correlations with treatment outcome and in vitro drug sensitivity. Blood 78: 586–592, 1991PubMedGoogle Scholar
  5. 5.
    Lum BL, Kaubisch S, Yahanda AM, Adler KM, Jew L, Ehsan MNAlterations of etoposide pharmacokinetics and pharmacodynamics by cyclosporine in a phase I trial to modulate multidrug resistance. J. Clin Oncol: 1635–42, 1992Google Scholar
  6. 6.
    Ho A, Lipp T, Ehninger G, et al: Combination mitoxantrone and etoposide in refractory AML- an active well-tolerated regimen J. Clin. Oncol.6: 213–217, 19887Google Scholar
  7. 7.
    Oseika R, Seeber S, Pannenbacker R, Soll D, Glatte P, and Schmidt CG: Enhancement of etoposide-induced cytotoxicity by cyclosporine A. Cancer Chemother Pharmacol. 18: 198–202, 1986CrossRefGoogle Scholar
  8. 8.
    Marie J-P, Bastie JN, Coloma F, Just-Landi S Filleul S, Catalina J, et al. A phase I-II trial of cyclosporine with etoposide and mitoxantrone in advanced acute leukemia. Proc Am Soc Clin Oncol 11: 275, 1992Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • G. V. Dahl
    • 1
  • N. Brophy
    • 2
  • H. Grier
    • 3
  • H. Weinstein
    • 3
  • B. Sikic
    • 2
  • R. Arceci
    • 3
  1. 1.Pediatric Hematology/Oncology DivisionStanford UniversityStanfordUSA
  2. 2.Medical OncologyStanford UniversityStanfordUSA
  3. 3.Pediatric OncologyDana-Farber Cancer InstituteBostonUSA

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