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Titolo:
Protection and in vivo selection of hematopoietic stem cells using temozolomide, O-6-benzylguanine, and an alkyltransferase-expressing retroviral vector
Autore:
Sawai, N; Zhou, S; Vanin, EF; Houghton, P; Brent, TP; Sorrentino, BP;
Indirizzi:
St Jude Childrens Res Hosp, Dept Hematol Oncol, Memphis, TN 38105 USA St Jude Childrens Res Hosp Memphis TN USA 38105 ol, Memphis, TN 38105 USA St Jude Childrens Res Hosp, Dept Mol Pharmacol, Memphis, TN 38105 USA St Jude Childrens Res Hosp Memphis TN USA 38105 ol, Memphis, TN 38105 USA
Titolo Testata:
MOLECULAR THERAPY
fascicolo: 1, volume: 3, anno: 2001,
pagine: 78 - 87
SICI:
1525-0016(200101)3:1<78:PAIVSO>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
DNA METHYLTRANSFERASE GENE; BONE-MARROW CELLS; GREEN FLUORESCENT PROTEIN; DRUG-RESISTANCE GENE; PHASE-I TRIAL; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; MEDIATED TRANSFER; PROGENITOR CELLS; TUMOR-CELLS; HUMAN MDR1;
Keywords:
hematopoietic stem cells; gene therapy; methylguanine-DNA methyltransferase; temozolomide; O-6-benzylguanine; retroviral vector; bone marrow transplantation;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
60
Recensione:
Indirizzi per estratti:
Indirizzo: Sorrentino, BP St Jude Childrens Res Hosp, Dept Hematol Oncol, 332 N Lauderdale, Memphis,TN 38105 USA St Jude Childrens Res Hosp 332 N Lauderdale Memphis TN USA 38105
Citazione:
N. Sawai et al., "Protection and in vivo selection of hematopoietic stem cells using temozolomide, O-6-benzylguanine, and an alkyltransferase-expressing retroviral vector", MOL THER, 3(1), 2001, pp. 78-87

Abstract

Transfer of drug resistance genes to hematopoietic stem cells offers the potential to protect cancer patients from drug-induced myelosuppression and to increase the number of gene-modified cells by in vivo selection. In thisstudy, a retroviral vector expressing both a P140K variant of human O-6-methylguanine-DNA methyltransferase (MCMT) and an EGFP reporter gene was evaluated for stem cell protection in a murine transplant model. Mice transplanted with vector-transduced cells showed significant resistance to the myelosuppressive effects of temozolomide (TMZ), an orally administered DNA-methylating drug, and O-6-benzylguanine (BC), a drug that depletes cells of wild-type MCMT activity. Following drug treatment, increases in EGFP(+) peripheral blood cells were seen in all peripheral blood lineages, and secondary transplant experiments proved that selection had occurred at the stem cell level. In a second set of experiments in which transduced cells were dilutedwith unmarked cells, efficient stem cell selection was noted together withprogressive marrow protection with repeated treatment courses. Altogether,these results show that P140K MCMT gene transfer can protect stem cells against the toxic effects of TMZ and Be; and that this vector/drug system maybe useful for clinical myeloprotection and for in vivo selection of transduced stem cells.

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Documento generato il 05/04/20 alle ore 08:35:48