Reduced Effect of Gemtuzumab Ozogamicin (CMA-676) on P-glycoprotein and/or CD34-positive Leukemia Cells and Its Restoration by Multidrug Resistance Modifiers

Leukemia. 2002 May;16(5):813-9. doi: 10.1038/sj.leu.2402459.

Abstract

Gemtuzumab ozogamicin (CMA-676), a calicheamicin-conjugated humanized anti-CD33 mouse monoclonal antibody, has recently been introduced clinically as a promising drug for the treatment of patients with acute myeloid leukemia (AML), more than 90% of which express CD33 antigen. However, our recent study suggested that CMA-676 was excreted by a multi- drug-resistance (MDR) mechanism in P-glycoprotein (P-gp)-expressing leukemia cell lines. We analyzed the in vitro effects of CMA-676 on leukemia cells from 27 AML patients in relation to the amount of P-gp, MDR-associated protein 1 (MRP1), CD33 and CD34, using a multi-laser-equipped flow cytometer. The cytocidal effect of CMA-676, estimated by the amount of hypodiploid portion on cell cycle, was inversely related to the amount of P-gp estimated by MRK16 monoclonal antibody (P = 0.004), and to the P-gp function assessed by intracellular rhodamine-123 accumulation in the presence of PSC833 or MS209 as a MDR modifier (P = 0.0004 and P = 0.002, respectively). In addition, these MDR modifiers reversed CMA-676 resistance in P-gp-expressing CD33(+) leukemia cells (P = 0.001 with PSC833 and P = 0.0007 with MS209). In CD33(+) AML cells from 13 patients, CMA-676 was less effective on CD33(+)CD34(+) than CD33(+)CD34(-) cells (P = 0.002). PSC833 partially restored the effect of CMA-676 in CD33(+)CD34(+) cells. These results suggest that the combined use of CMA-676 and a MDR modifier will be more effective on CD33(+) AML with P-gp-related MDR.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / analysis*
  • Acute Disease
  • Adult
  • Aged
  • Aged, 80 and over
  • Aminoglycosides*
  • Anti-Bacterial Agents / pharmacology*
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • Antigens, CD / analysis
  • Antigens, CD / immunology
  • Antigens, CD34 / analysis*
  • Antigens, Differentiation, Myelomonocytic / analysis
  • Antigens, Differentiation, Myelomonocytic / immunology
  • Cell Cycle / drug effects
  • Cyclosporins / pharmacology
  • Drug Interactions
  • Drug Resistance, Neoplasm*
  • Female
  • Gemtuzumab
  • Humans
  • Immunotoxins / pharmacology
  • Leukemia, Myeloid / immunology
  • Leukemia, Myeloid / metabolism
  • Leukemia, Myeloid / pathology*
  • Male
  • Middle Aged
  • Quinolines / pharmacology
  • Sialic Acid Binding Ig-like Lectin 3
  • Tumor Cells, Cultured

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Aminoglycosides
  • Anti-Bacterial Agents
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antigens, CD
  • Antigens, CD34
  • Antigens, Differentiation, Myelomonocytic
  • CD33 protein, human
  • Cd33 protein, mouse
  • Cyclosporins
  • Immunotoxins
  • Quinolines
  • Sialic Acid Binding Ig-like Lectin 3
  • dofequidar
  • Gemtuzumab
  • valspodar