Document Detail

Multidrug transporter proteins and cellular factors involved in free and mAb linked calicheamicin-gamma1 (gentuzumab ozogamicin, GO) resistance and in the selection of GO resistant variants of the HL60 AML cell line.
MedLine Citation:
PMID:  20428776     Owner:  NLM     Status:  MEDLINE    
In this study we elucidated the role of ATP-binding cassette (ABC) multi-drug transporter proteins and cellular factors such as Bcl-2 expression and CD33 down-modulation contributing to free and hP67.6 mAb linked calicheamicin-gamma1 (CalC-gamma1) resistance. We analyzed in a well designed HL60 cell system the relationship between the expression of ABC proteins, Bcl-2 and CD33 modulation with the activity of free and mAb-linked CalC-gamma1. The results herein reported and discussed, strongly suggest that both MDR1-Pgp and MRP1 efflux systems are engaged by CalC-gamma1, but only MDR1-Pgp over-expression efficiently abrogates drug cytotoxicity in MDR cells. Paradoxically, Bcl-2 expression, as observed for other anticancer compounds belonging to the enediyne family of drugs, confers CalC-gamma1 susceptibility rather than resistance in HL60 cells. Further, the isolation of a resistant HL60 subline (HL60AL) that was developed by exposing the parental sensitive cells to sub-effective doses of gemtuzumab ozogamicin (GO) over an extended period of time shows a reduced level of CD33 expression that represents an important escape mechanism of HL60 MDR cells to the cytotoxic effect of GO.
Maurizio Cianfriglia; Alessandra Mallano; Alessandro Ascione; Maria Luisa Dupuis
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of oncology     Volume:  36     ISSN:  1791-2423     ISO Abbreviation:  Int. J. Oncol.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-04-29     Completed Date:  2010-08-20     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9306042     Medline TA:  Int J Oncol     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  1513-20     Citation Subset:  IM    
Section of Pharmacogenetics, Drug Resistance and Experimental Therapeutics, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
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MeSH Terms
Aminoglycosides / pharmacology*
Antibiotics, Antineoplastic / pharmacology*
Antibodies, Monoclonal / pharmacology*
Antigens, CD / genetics,  metabolism
Antigens, Differentiation, Myelomonocytic / genetics,  metabolism
Apoptosis / drug effects
Blotting, Western
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Resistance, Neoplasm / genetics*
Enediynes / pharmacology*
Multidrug Resistance-Associated Proteins / biosynthesis,  genetics*
P-Glycoprotein / biosynthesis,  genetics*
Proto-Oncogene Proteins c-bcl-2 / genetics,  metabolism
Reg. No./Substance:
0/Aminoglycosides; 0/Antibiotics, Antineoplastic; 0/Antibodies, Monoclonal; 0/Antigens, CD; 0/Antigens, Differentiation, Myelomonocytic; 0/CD33 antigen; 0/Enediynes; 0/Multidrug Resistance-Associated Proteins; 0/P-Glycoprotein; 0/Proto-Oncogene Proteins c-bcl-2; 0/gemtuzumab; 0/multidrug resistance-associated protein 1; 108212-75-5/calicheamicin gamma(1)I

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