Reduced effect of gemtuzumab ozogamicin (CMA-676) on P-glycoprotein and/or CD34-positive leukemia cells and its restoration by multidrug resistance modifiers.
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.
Matsui
H
H
Division of Hematology, Department of Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Hamamatsu-shi, 431-3192 Japan.
Takeshita
A
A
Naito
K
K
Shinjo
K
K
Shigeno
K
K
Maekawa
M
M
Yamakawa
Y
Y
Tanimoto
M
M
Kobayashi
M
M
Ohnishi
K
K
Ohno
R
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis*; D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000032:analysis / Q000276:immunology; D018952:Antigens, CD34 / Q000032:analysis*; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis / Q000276:immunology; D002453:Cell Cycle / Q000187:drug effects; D003524:Cyclosporins / Q000494:pharmacology; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D005260:Female; D000079982:Gemtuzumab; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000494:pharmacology; D063268:Sialic Acid Binding Ig-like Lectin 3; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D018952:Antigens, CD34; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; C571165:Cd33 protein, mouse; D003524:Cyclosporins; D000922:Immunotoxins; D011804:Quinolines; D063268:Sialic Acid Binding Ig-like Lectin 3; C087719:dofequidar; D000079982:Gemtuzumab; C070272:valspodar