P-gp activity is a critical resistance factor against AVE9633 and DM4 cytotoxicity in leukaemia cell lines, but not a major ... View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2009-06-23

AUTHORS

Ruoping Tang, Simy Cohen, Jean-Yves Perrot, Anne-Marie Faussat, Claudia Zuany-Amorim, Zora Marjanovic, Hamid Morjani, Fanny Fava, Elise Corre, Ollivier Legrand, Jean-Pierre Marie

ABSTRACT

BackgroundAVE9633 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).MethodsThis 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.ResultsP-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 (IC50 > 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.ConclusionP-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. More... »

PAGES

199

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/1471-2407-9-199

DOI

http://dx.doi.org/10.1186/1471-2407-9-199

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1020277867

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/19549303


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28 schema:description BackgroundAVE9633 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).MethodsThis 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.ResultsP-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 (IC50 > 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.ConclusionP-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.
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36 ABC proteins
37 AML cell lines
38 AML cells
39 AML patients
40 BCRP
41 BCRP protein
42 CD33 expression
43 DM4
44 GP activity
45 MRP1
46 MTT
47 MethodsThis study
48 P-gp
49 P-gp activity
50 P-gp inhibitors
51 activity
52 acute myeloid leukemia
53 acute myeloid leukemia patients
54 agents
55 aim
56 alterations
57 anti-mitotic agents
58 antibodies
59 antigen
60 apoptosis assays
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62 bonds
63 cell lines
64 cells
65 chemoresistance
66 clinical trials
67 combination
68 critical resistance factor
69 crucial mechanism
70 cytometry
71 cytotoxic agents
72 cytotoxicity
73 data
74 different levels
75 disulfide bonds
76 drug sensitivity
77 drugs
78 expression
79 factors
80 flow cytometry
81 functionality
82 humanized monoclonal antibody
83 immunoconjugates
84 important role
85 inhibitors
86 leukemia
87 leukemia cell lines
88 leukemia patients
89 levels
90 lines
91 major mechanism
92 mechanism
93 microtubule alterations
94 monoclonal antibodies
95 myeloid cell lines
96 myeloid leukemia
97 myeloid leukemia patients
98 new immunoconjugates
99 overexpression
100 part
101 patients
102 phase I clinical trial
103 potent tubulin inhibitors
104 potential role
105 present study
106 protein
107 protein expression
108 resistance
109 resistance factor
110 role
111 samples
112 sensitivity
113 sensitivity of cells
114 specific P-gp inhibitor
115 study
116 transporter proteins
117 trials
118 tubulin inhibitors
119 zosuquidar
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