Abstract |
Resistance to gemtuzumab ozogamicin (GO) hampers the effective treatment of refractory acute myeloid leukemia (AML). To clarify the mechanism of resistance to GO, HL-60 cells were persistently exposed to GO in order to establish GO-resistant HL-60 (HL-60/GOR) cells. Multidrug resistance 1 (MDR-1) was strongly expressed in HL-60/GOR cells, but not in HL-60 cells. Although withdrawal of GO after the chronic exposure of HL-60/GOR cells to this compound gradually decreased MDR-1 expression to trace levels, reintroducing GO restored high MDR-1 expression in HL-60/GOR cells, but not in HL-60 cells. These results indicate that HL-60/GOR cells acquired the ability to induce MDR-1 expression in response to GO. U0126, a MEK1/2 inhibitor, prevented GO-inducible MDR-1 expression and abrogated GO resistance in HL-60/GOR cells. These results suggest that in the clinical use of GO, inducible MDR-1 expression in tumor cells should be investigated before treatment with GO. If the cells are positive then MEK1/2 inhibitors may be effective in overcoming resistance to GO.
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Authors | Taichi Matsumoto, Shiro Jimi, Shuuji Hara, Yasushi Takamatsu, Junji Suzumiya, Kazuo Tamura |
Journal | Leukemia & lymphoma
(Leuk Lymphoma)
Vol. 53
Issue 7
Pg. 1399-405
(Jul 2012)
ISSN: 1029-2403 [Electronic] United States |
PMID | 22242821
(Publication Type: Journal Article)
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Chemical References |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Aminoglycosides
- Antibodies, Monoclonal, Humanized
- Antineoplastic Agents
- Butadienes
- Nitriles
- U 0126
- Gemtuzumab
- MAP2K2 protein, human
- MAP Kinase Kinase 1
- MAP Kinase Kinase 2
- MAP2K1 protein, human
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Topics |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(genetics)
- Aminoglycosides
(pharmacology)
- Antibodies, Monoclonal, Humanized
(pharmacology)
- Antineoplastic Agents
(pharmacology)
- Blotting, Western
- Butadienes
(pharmacology)
- Cell Survival
(drug effects, genetics)
- Dose-Response Relationship, Drug
- Drug Resistance, Neoplasm
(drug effects, genetics)
- Flow Cytometry
- Gemtuzumab
- Gene Expression Regulation, Leukemic
(drug effects)
- HL-60 Cells
- Humans
- Leukemia, Promyelocytic, Acute
(genetics, metabolism, pathology)
- MAP Kinase Kinase 1
(antagonists & inhibitors, metabolism)
- MAP Kinase Kinase 2
(antagonists & inhibitors, metabolism)
- Nitriles
(pharmacology)
- Reverse Transcriptase Polymerase Chain Reaction
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