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Titolo:
Generation of dual resistance to 4-hydroperoxycyclophosphamide and methotrexate by retroviral transfer of the human aldehyde dehydrogenase class 1 gene and a mutated dihydrofolate reductase gene
Autore:
Takebe, N; Zhao, SC; Adhikari, D; Mineishi, S; Sadelain, M; Hilton, J; Colvin, M; Banerjee, D; Bertino, JR;
Indirizzi:
Sloan Kettering Inst, Dept Med, New York, NY 10021 USA Sloan Kettering Inst New York NY USA 10021 pt Med, New York, NY 10021 USA Sloan Kettering Inst, Program Mol Pharmacol & Expt Therapeut, New York, NY10021 USA Sloan Kettering Inst New York NY USA 10021 erapeut, New York, NY10021 USA Mem Sloan Kettering Canc Ctr, Dept Human Genet, New York, NY 10021 USA MemSloan Kettering Canc Ctr New York NY USA 10021 New York, NY 10021 USA Johns Hopkins Oncol Ctr, Baltimore, MD 21231 USA Johns Hopkins Oncol Ctr Baltimore MD USA 21231 r, Baltimore, MD 21231 USA Duke Univ, Med Ctr, Ctr Comprehens Canc, Durham, NC 27710 USA Duke Univ Durham NC USA 27710 , Ctr Comprehens Canc, Durham, NC 27710 USA
Titolo Testata:
MOLECULAR THERAPY
fascicolo: 1, volume: 3, anno: 2001,
pagine: 88 - 96
SICI:
1525-0016(200101)3:1<88:GODRT4>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
HEMATOPOIETIC PROGENITOR CELLS; LONG-TERM PROTECTION; BONE-MARROW CELLS; MEDIATED TRANSFER; IN-VITRO; STEM-CELLS; HUMAN MDR1; SELECTION; CDNA; VIVO;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
37
Recensione:
Indirizzi per estratti:
Indirizzo: Bertino, JR Sloan Kettering Inst, Dept Med, 1275 York Ave 78, New York, NY10021 USA Sloan Kettering Inst 1275 York Ave 78 New York NY USA 10021 SA
Citazione:
N. Takebe et al., "Generation of dual resistance to 4-hydroperoxycyclophosphamide and methotrexate by retroviral transfer of the human aldehyde dehydrogenase class 1 gene and a mutated dihydrofolate reductase gene", MOL THER, 3(1), 2001, pp. 88-96

Abstract

The genetic transfer of drug resistance to hematopoietic cells is an attractive approach to overcoming myelosuppression caused by high-dose chemotherapy. Because cyclophosphamide (CTX) and methotrexate (MTX) are commonly used non-cross-resistant drugs, generation of dual drug resistance in hematopoietic cells that allows dose intensification may increase anti-tumor effects and circumvent the emergence of drug-resistant tumors. We constructed a retroviral vector containing both a human cytosolic ALDH-1 cDNA and a human doubly mutated DHFR cDNA (Phe22/Ser31; termed F/s in the description of constructs) to generate increased resistance to both CTX and MTX. Infection ofNIH3T3 cells resulted in increased resistance to both 4-hydroperoxy-cyclophosphamide (4HC) (1.9 +/- 0.1-fold) and MTX (73 +/- 2.8-fold). Transduced human CD34(+) enriched hematopoietic progenitor cells were also resistant toboth 4HC and MTX by CFU-GM readout. Lethally irradiated mice transplanted with SFG-ALDH-IREs-F/S or mock-transduced bone marrow cells were treated with high-dose pulse CTX or high-dose CTX/MTX. Animals receiving marrow not transduced with ALDH-1 or mutated DHFR cDNA died from CTX or CTX/MTX toxicity, whereas mice transduced with ALDH-1 and mutated DHFR cDNA-containing marrow were able to tolerate the same doses of CTX or CTX/MTX treatment posttransplant. These data taken together indicate that ALDH-1 overexpression andmutant DHFR increased both 4HC and MTX resistance in vitro and in the in vivo mouse model. This construct may be useful for protecting patients from high-dose CTX- and MTX-induced myelosuppression.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 01/04/20 alle ore 11:15:26