A novel dual function retrovirus expressing multidrug resistance 1 and O6-alkylguanine-DNA-alkyltransferase for engineering resistance of haemopoietic progenitor cells to multiple chemotherapeutic agents.
Rafferty, Joseph A
Lashford, Linda S
Margison, Geoffrey P
Dexter, T Michael
Fairbairn, Leslie J
AffiliationInstitute of Haematology and Blood Transfusion, Praha, Czech Republic.
MetadataShow full item record
AbstractFollowing transduction with a retrovirus (SF1MIH) expressing both the multidrug resistance 1 (MDR1) and O6-alkylguanine-DNA-alkyltransferase (ATase) proteins, human erythroleukaemic progenitor (K562) cells were isolated which were resistant to killing by the MDR1 substrate, colchicine. In colony-forming survival assays, K562-SF1MIH cells exhibited resistance to colchicine and doxorubicin, as well as to the O6-alkylating agents N-Methyl-N-nitrosourea (MNU) and temozolomide. Furthermore, the resistance to doxorubicin was abolished by preincubation with the MDR1 inhibitor verapamil while resistance to MNU was ablated by the specific ATase inactivator, O6-benzylguanine (O6-beG) confirming that resistance to doxorubicin and MNU was conferred by MDR1 and ATase, respectively. When K562-SF1MIH were exposed to combinations of colchicine and MNU or doxorubicin and temozolomide, simultaneous resistance to these agents was observed. Thus, transduction of K562 with SF1MIH conferred dual resistance to these cells. These data offer the prospect of designing vectors that will confer resistance to entire regimens of chemotherapy rather than just to individual components of such drug cocktails, thereby substantially increasing the efficacy of therapy. Furthermore, the use of such dual expression constructs is likely to be highly informative for the design of effective in vivo selection protocols, an issue likely to make a major impact in a clinical context in gene therapy in the near future.
CitationA novel dual function retrovirus expressing multidrug resistance 1 and O6-alkylguanine-DNA-alkyltransferase for engineering resistance of haemopoietic progenitor cells to multiple chemotherapeutic agents. 1999, 6 (8):1489-93 Gene Ther.
- Dual agent chemoprotection by retroviral co-expression of either MDR1 or MRP1 with the P140K mutant of O6-methylguanine-DNA-methyl transferase.
- Authors: Southgate TD, Garside E, Margison GP, Fairbairn LJ
- Issue date: 2006 Aug
- Retroviral coexpression of two different types of drug resistance genes to protect normal cells from combination chemotherapy.
- Authors: Suzuki M, Sugimoto Y, Tsukahara S, Okochi E, Gottesman MM, Tsuruo T
- Issue date: 1997 Jun
- Chemoprotective gene transfer I: transduction of human haemopoietic progenitors with O6-benzylguanine-resistant O6-alkylguanine-DNA alkyltransferase attenuates the toxic effects of O6-alkylating agents in vitro.
- Authors: Hickson I, Fairbairn LJ, Chinnasamy N, Lashford LS, Thatcher N, Margison GP, Dexter TM, Rafferty JA
- Issue date: 1998 Jun
- Long-term protection of hematopoiesis against the cytotoxic effects of multiple doses of nitrosourea by retrovirus-mediated expression of human O6-alkylguanine-DNA-alkyltransferase.
- Authors: Jelínek J, Fairbairn LJ, Dexter TM, Rafferty JA, Stocking C, Ostertag W, Margison GP
- Issue date: 1996 Mar 1
- Retroviral transduction and expression of the human alkyltransferase cDNA provides nitrosourea resistance to hematopoietic cells.
- Authors: Allay JA, Dumenco LL, Koc ON, Liu L, Gerson SL
- Issue date: 1995 Jun 1