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Dual agent chemoprotection by retroviral co‐expression of either MDR1 or MRP1 with the P 140 K mutant of O 6 ‐methylguanine‐DNA‐methyl transferase
Author(s) -
Southgate Thomas D.,
Garside Elloise,
Margison Geoffrey P.,
Fairbairn Leslie J.
Publication year - 2006
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.914
Subject(s) - haematopoiesis , mutant , cancer research , biology , abcg2 , atp binding cassette transporter , in vivo , mutation , methyltransferase , dna , chemistry , pharmacology , microbiology and biotechnology , transporter , gene , genetics , stem cell , methylation
Tumour resistance to chemotherapeutic agents results in most chemotherapy being administered in a multi‐agent fashion that is often associated with a high level of toxicity in highly proliferative tissues such as the haematopoietic compartment. Thus, whilst many genetic manipulation strategies aim to protect normal tissue against a single component of a multi‐agent regime, it is clearly preferable to protect normal cells against all toxicities. In this study we have used retroviral gene transfer to achieve co‐expression of either p‐glycoprotein (MDR1) or multi‐drug resistance‐related protein 1 (MRP1) with the P 140 K mutant form of O 6 ‐methylguanine‐DNA‐methyl transferase (MGMT) which, unlike the wild‐type protein, is insensitive to inactivation by tumour sensitisers such as O 6 ‐benzylguanine ( O 6 ‐BeG) or PaTrin2. The combination of certain MDR1/MRP1 substrate drugs with O 6 ‐alkylating agents (against which MGMT confers resistance) is particularly myelotoxic. We show here that haematopoietic progenitors co‐expressing mutant MGMT with an ABC‐transporter exhibit resistance to combination chemotherapy in vitro . This combination of drug transporter and DNA repair function may provide an effective in vivo protection of the haematopoietic compartment during tumour ablation using combination chemotherapy. Copyright © 2006 John Wiley & Sons, Ltd.