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Titolo:
Human long-term culture initiating cells are sensitive to benzylguanine and 1,3-bis (2-chloroethyl)-1-nitrosourea and protected after mutant (G156A) methylguanine methyltransferase gene transfer
Autore:
Koc, ON; Reese, JS; Szekely, EM; Gerson, SL;
Indirizzi:
Case Western Reserve Univ Hosp, Ireland Canc Ctr, Div Hematol Oncol, Cleveland, OH 44106 USA Case Western Reserve Univ Hosp Cleveland OH USA 44106 eland, OH 44106 USA
Titolo Testata:
CANCER GENE THERAPY
fascicolo: 4, volume: 6, anno: 1999,
pagine: 340 - 348
SICI:
0929-1903(199907/08)6:4<340:HLCICA>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
HEMATOPOIETIC STEM-CELLS; HUMAN O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; PROGENITOR CELLS; PERIPHERAL-BLOOD; O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; AUTOLOGOUS TRANSPLANTATION; RETROVIRAL TRANSDUCTION; DIHYDROFOLATE-REDUCTASE; NITROSOUREA RESISTANCE; COMPLEMENTARY-DNA;
Keywords:
drug resistance; hematopoietic gene transfer; long-term culture initiating cells;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
45
Recensione:
Indirizzi per estratti:
Indirizzo: Koc, ON Case Western Reserve Univ, Dept Med, Sch Med, 10900 Euclid Ave, Cleveland,OH 44106 USA Case Western Reserve Univ 10900 Euclid Ave Cleveland OH USA 44106
Citazione:
O.N. Koc et al., "Human long-term culture initiating cells are sensitive to benzylguanine and 1,3-bis (2-chloroethyl)-1-nitrosourea and protected after mutant (G156A) methylguanine methyltransferase gene transfer", CANC GENE T, 6(4), 1999, pp. 340-348

Abstract

Human hematopoietic progenitors express low levels of O-6-alkylguanine-DNAalkyltransferase and are sensitive to 1,3-bis(2-chloroethyl)-1-nitrosourea(BCNU), particularly following O-6-benzylguanine (BG)-mediated O-6-alkylguanine-DNA alkyltransferase inhibition. Expression of the BC-resistant mutant (C156A) methylguanine methyltransferase (Delta MGMT) gene in hematopoietic cells confers resistance to BG and BCNU. Because BCNU targets both early and late human hematopoietic cells and results in prolonged and cumulative myelosuppression, we attempted to protect early hematopoietic progenitors (long-term culture initiating cells (LTC-ICs)) by retroviral-mediated transfer of the Delta MGMT gene. A total of 33-56% of LTC-ICs were transduced with MFG-Delta MGMT retrovirus as determined by evidence of provirus in secondary colony-forming units at 5 weeks of culture under conditions optimal forthe survival and proliferation of early hematopoietic progenitors. The addition of flt-3 ligand to cultures increased the transduction rate of LTC-ICs. Furthermore, 17.8 +/- 8.1% of Delta MGMT-transduced LTC-ICs survived doses of BG and BCNU; these doses allowed the survival of only 0-1% of untransduced LTC-ICs. This finding compares favorably with the 8-12% of CD34(+) cell-derived colony-forming units that we previously showed became resistant to BG and BCNU after Delta MGMT gene transfer. Thus, Delta MGMT transduction of human early hematopoietic progenitor LTC-ICs confers resistance to BC and BCNU and may allow transduced LTC-ICs selective survival and enrichmentover untransduced cells in patients undergoing BC and BCNU chemotherapy.

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Documento generato il 01/10/20 alle ore 07:38:34