Approaches to Overcome Multidrug Resistance: PSC and CdA/ara-C Combination Chemotherapy

  • G. Juliusson
Part of the Haematology and Blood Transfusion / Hämatologie und Bluttransfusion book series (HAEMATOLOGY, volume 39)


Multidrug resistance (MDR) is a potential major problem in acute myeloid leukemia (AML). Approaches to overcome MDR include pharmacological reversal of P-glycoprotein-mediated resistance, and use of effective drugs not affected by MDR, such as nucleoside analogues. Drugs that confer reversal of MDR in vitro include verapamil and cyclosporin A. We have analysed concentrations of anthracyclins and their metabolites within leukemic cells in vivo during continuous infusion of doxorubicin, daunorubicin, and idarubicin, respectively, and documented an elevated steady state level of active metabolites during concomitant treatment with verapamil, and cyclosporina A (CyA).

In a Scandinavian phase I/II study, the CyA analogue PSC833 was given together with daunorubicin and cytosin arabinoside (ara-C) to patients with refractory or relapsing AML to assess a feasible dose level of PSC and daunorubicin. The overall CR rate in 41 patients during the dose finding part of the study was 27%. Patient recruitment into the phase II part continues using a PSC dose of 10 mg/kg/day on days 1–4, and daunorubicin 45 mg/sqm/day on days 1–3, with ara-C 1 g/sqm/2h q 12 h, days 1–4.

2-Chlorodeoxyadenosine (Cladribine, CdA) is a purine analogue with a documented single-drug activity in de novo and relapsed pediatric AML. In analogy with the studies on fludarabine/ara-C combinations, we evaluated ara-CTP concentrations in AML cells during ara-C treatment with or without CdA pretreatment. Priming with CdA gave a 36% median increase in ara-CTP concentrations. Thirty patients (AML n = 21, ALL n = 4, MDS n = 1, MDS-AML n = 4; previously untreated n = 20, previously treated n = 10, 4 of them with relapse following stem cell transplants), aged 20–76 years (median 47 yrs), were given a combination of CdA, ara-C and idarubicin. The overall CR rate from one course was 73%, and among previously untreated patients 85%. Toxicity was limited, and recovery from thrombocytopenia (> 50) and neutropenia (> 0.5) was prompt and occurred on day 21 and 23 from start of treatment (median), respectively. The projected 3-year survival of the 20 previously untreated cases is 70% (with 4 auto-transplants, and 6 allogeneic stem cell transplants during follow-up). CR rate and overall survival in refractory patients were not as encouraging.


Acute Myeloid Leukemia Acute Myeloid Leukemia Patient Acute Myeloid Leukemia Cell Pediatric Acute Myeloid Leukemia Lung Resistance Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Sonneveld P (1996) Multidrug resistance in acute myeloid leukaemia. Baillière’s Clinical Haematology 9: 185–203CrossRefGoogle Scholar
  2. 2.
    List AF (1996) Role of multidrug resistance and its pharmacological modulation in acute myeloid leukemia. Leukemia 10: 937–942PubMedGoogle Scholar
  3. 3.
    Gandhi V, Estey E, Keating MJ, Plunkett W (1993) Fludarabine potentiates metabolism of arabinosylcytosine in patients with acute myeloid leukemia during therapy. J Clin Oncol 11: 116–124PubMedGoogle Scholar
  4. 4.
    Warrell RP Jr, Berman E (1986) Phase I and II study of fludarabine phosphate in leukemia: therapeutic efficacy with delayed central nervous toxicity. J Clin Oncol 4: 74PubMedGoogle Scholar
  5. 5.
    SantanaVM,MiroJJr,KearnsC,SchellMJ,Crom W, Blakely RL (1992) 2-Chlorodeoxyadenosine produces a high rate of complete hematologic remission in relapsed acute myeloid leukemia. J Clin Oncol 10: 364–370Google Scholar
  6. 6.
    Santana VM, Hurwitz CA, Blakley RL, Crom WR, Luo X, Roberts WM, Ribeiro R, Mahmoud H, Krance RA (1994) Complete hematologic remission induced by 2-chlorodeoxyadenosine in children with newly diagnosed acute myeloid leukemia. Blood 84: 1237–1242PubMedGoogle Scholar
  7. 7.
    Ribeiro RC, Santana VM, Head D, Jayawardene D, Srivastava DK, Raimondi S, Hurwitz CA, Mahmoud H, Krance R (1996) Factors associated with hematologic response to 2-chlorodeoxyadenoaine (2-CdA) in de novo pediatric acute myeloid leukemia. Blood 88 (Suppl 1): 219aGoogle Scholar
  8. 8.
    Liliemark J, Juliusson G (1992) On the pharmacokinetics of 2-chloro-2’-deoxyadenosine (CdA) in cerebrospinal fluid (CSF). Blood 80 (suppl): 471aGoogle Scholar
  9. 9.
    Tidefelt U, Juliusson G, Elmhorn-Rosenborg A, Peterson C, Paul C (1994) Increased intracellular concentrations of doxorubicin in resistant lymphoma cells in vivo by concomitant therapy with verapamil and cyclosporin A. Eur J Haematol 52: 276–282PubMedCrossRefGoogle Scholar
  10. 10.
    Liliemark J, Björkholm M, Udén A-M, Hast R, Paul C, Simonsson B, Tidefelt U, Juliusson G, Hedenus M, Evensen S, Tangen JM, Sjo M, Nesthus I, Hestdal K (1996) A phase I/II study of SDZ PSC 833 in combination with daunorubicin and cytarabine in refractory acute myelogeneous leukemia. Blood 88 (suppl 1): 216aGoogle Scholar
  11. 11.
    Juliusson G, Liliemark J (1994) 2-Chlorodeoxyadenosine (CdA) with and without cytosin arabinoside (ara-C) and idarubicin for acute myeloid and lymphoid leukemia - clinical and pharmacokinetic studies. Br J Haematol 87 (suppl 1 ): 12Google Scholar
  12. 12.
    Gandhi V, Estey E, Keating MJ, Chucrullah, Plunckett W (1996) Chlorodeoxyadenosine and arabinosylcytosine in patients with acute myelogeneous leukemia: pharmacokinetic, pharmacodynamic, and molecular interactions. Blood 87: 256–264PubMedGoogle Scholar
  13. 13.
    Vandat L, Wong ET, Wile MJ, Rosenblum M, Foley KM, Warrell RP Jr (1994) Therapeutic and neurotoxic effects of 2-chlorodeoxyadenosine in adults with acute myeloid leukemia. Blood 84: 3429–3434Google Scholar
  14. 14.
    Kornblau SM, Gandhi V, Andreeff HM, Beran M, Kantarjian HM, Koller CA, O’Brien S, Plunkett W, Estey E (1996) Clinical and laboratory studies of 2-chlorodeoxyadenosine ± cytosine arabinoside for relapsed or refractory acute myelogeneous leukemia in adults. Leukemia 10: 1563–1569PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • G. Juliusson
    • 1
  1. 1.Department of HematologyUniversity HospitalLinköpingSweden

Personalised recommendations