P-gp activity is a critical resistance factor against AVE9633 and DM4 cytotoxicity in leukaemia cell lines, but not a major mechanism of chemoresistance in cells from acute myeloid leukaemia patients

BMC Cancer. 2009 Jun 23;9:199. doi: 10.1186/1471-2407-9-199.

Abstract

Background: AVE9633 is a new immunoconjugate comprising a humanized monoclonal antibody, anti-CD33 antigen, linked through a disulfide bond to the maytansine derivative DM4, a cytotoxic agent and potent tubulin inhibitor. It is undergoing a phase I clinical trial. Chemoresistance to anti-mitotic agents has been shown to be related, in part, to overexpression of ABC proteins. The aim of the present study was to investigate the potential roles of P-gp, MRP1 and BCRP in cytotoxicity in AVE9633-induced acute myeloid leukaemia (AML).

Methods: This study used AML cell lines expressing different levels of P-gp, MRP1 or BCRP proteins and twenty-five samples from AML patients. Expression and functionality of the transporter protein were analyzed by flow cytometry. The cytotoxicity of the drug was evaluated by MTT and apoptosis assays.

Results: P-gp activity, but not MRP1 and BCRP, attenuated AVE9633 and DM4 cytotoxicity in myeloid cell lines. Zosuquidar, a potent specific P-gp inhibitor, restored the sensitivity of cells expressing P-gp to both AVE9633 and DM4. However, the data from AML patients show that 10/25 samples of AML cells (40%) were resistant to AVE9633 or DM4 (IC(50) > 500 nM), and this was not related to P-gp activity (p-Value: 0.7). Zosuquidar also failed to re-establish drug sensitivity. Furthermore, this resistance was not correlated with CD33 expression (p-Value: 0.6) in those cells.

Conclusion: P-gp activity is not a crucial mechanism of chemoresistance to AVE9633. For patients whose resistance to conventional anthracycline AML regimens is related to ABC protein expression, a combination with AVE9633 could be beneficial. Other mechanisms such as microtubule alteration could play an important role in chemoresistance to AVE9633.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / metabolism
  • Antibodies, Monoclonal / pharmacology
  • Antigens, CD / biosynthesis
  • Antigens, CD / immunology
  • Antigens, Differentiation, Myelomonocytic / biosynthesis
  • Antigens, Differentiation, Myelomonocytic / immunology
  • Dibenzocycloheptenes / pharmacology
  • Drug Resistance, Neoplasm
  • HL-60 Cells
  • Humans
  • Immunoconjugates / pharmacokinetics
  • Immunoconjugates / pharmacology*
  • K562 Cells
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / metabolism*
  • Maytansine / analogs & derivatives*
  • Maytansine / pharmacokinetics
  • Multidrug Resistance-Associated Proteins / metabolism
  • Neoplasm Proteins / metabolism
  • Quinolines / pharmacology
  • Sialic Acid Binding Ig-like Lectin 3

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antibodies, Monoclonal
  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD33 protein, human
  • Dibenzocycloheptenes
  • Immunoconjugates
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Quinolines
  • Sialic Acid Binding Ig-like Lectin 3
  • Maytansine
  • zosuquidar trihydrochloride
  • multidrug resistance-associated protein 1