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Titolo:
Direct reversal of DNA damage by mutant methyltransferase protein protectsmice against dose-intensified chemotherapy and leads to in vivo selection of hematopoietic stem cells
Autore:
Ragg, S; Xu-Welliver, M; Bailey, J; DSouza, M; Cooper, R; Chandra, S; Seshadri, R; Pegg, AE; Williams, DA;
Indirizzi:
Indiana Univ, Sch Med, Howard Hughes Med Inst, Sect Pediat Hematol Oncol, Indianapolis, IN 46202 USA Indiana Univ Indianapolis IN USA 46202 Oncol, Indianapolis, IN 46202 USA Indiana Univ, Sch Med, Herman No Wells Ctr Pediat Res, Dept Pediat, Indianapolis, IN 46202 USA Indiana Univ Indianapolis IN USA 46202 Pediat, Indianapolis, IN 46202 USA Indiana Univ, Sch Med, Dept Med, Div Biostat, Indianapolis, IN 46202 USA Indiana Univ Indianapolis IN USA 46202 iostat, Indianapolis, IN 46202 USA Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA Penn State Univ Hershey PA USA 17033 & Mol Physiol, Hershey, PA 17033 USA
Titolo Testata:
CANCER RESEARCH
fascicolo: 18, volume: 60, anno: 2000,
pagine: 5187 - 5195
SICI:
0008-5472(20000915)60:18<5187:DRODDB>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
RESISTANT BONE-MARROW; MAMMALIAN O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; RETROVIRUS-MEDIATED EXPRESSION; HUMAN TUMOR-CELLS; O-6-METHYLGUANINE-DNA METHYLTRANSFERASE; GENE-TRANSFER; IN-VIVO; FIBRONECTIN FRAGMENTS; ALKYLATING-AGENTS; REPAIR PROTEIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
54
Recensione:
Indirizzi per estratti:
Indirizzo: Williams, DA Indiana Univ, Inst Canc Res, Herman B Wells Ctr Pediat Res, 1044 W Walnut St 414, Indianapolis, IN 46202 USA Indiana Univ 1044 W Walnut St 414 Indianapolis IN USA 46202 A
Citazione:
S. Ragg et al., "Direct reversal of DNA damage by mutant methyltransferase protein protectsmice against dose-intensified chemotherapy and leads to in vivo selection of hematopoietic stem cells", CANCER RES, 60(18), 2000, pp. 5187-5195

Abstract

Direct reversal of O-6 adducts caused by chemotherapy agents is accomplished in mammalian cells by the protein O-6-methylguanine DNA methyltransferase (MGMT). Some tumors overexpress MGMT and are resistant to alkylator therapy, One future approach to treatment of these tumors may rely on concurrentpharmacological depletion of tumor MGMT with O-6-benzylguanine (6-BG) and protection of sensitive tissues, such as hematopoietic stem and progenitor cells, using genetic modification with 6-BG-resistant MGMT mutants. We haveused retroviral-mediated gene transfer to transduce murine hematopoietic bone marrow cells with MGMT point mutants showing resistance to 6-BG depletion irt vitro. These mutants include proline to alanine and proline to lysine substitutions at the 140 position (P140A and P140K, respectively), which show 40- and 1000-fold resistance to 6-BG compared with wild-type (WT) MGMT, Lethally irradiated mice were reconstituted with murine stem cells transduced with murine stem cell virus retrovirus expressing each mutant, WT MGMT, or mock-infected cells and then treated with a combination of 30 mg/kg 6-BG and 10 mg/kg 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or with 40 mg/kg BCNU alone, Compared with mice treated with BCNU alone, significant myeloid toxicity and death occurred in mice reconstituted with mock-infected or WT MGMT (<0.1 probability of survival) or the P140A mutant (0.13 probability of survival) MGMT cDNAs, In contrast, after an initial period of mild cytopenia, mice reconstituted with the P140K mutant (0.83 probability of survival) recovered nearly normal blood counts, even during continued treatment. Comparison of peripheral blood neutrophils after completion of 5 weekly treatments in these animals showed a direct correlation between the treatmentand in vivo selection for progeny of transduced cells (pretreatment, similar to 8-12% transduced cells; no treatment, similar to 6% transduced cells;BCNU only, 51% transduced cells; 6-BG/BCNU, 93% transduced cells), To determine whether this selection occurred at the stem cell level, bone marrow from each treatment group was infused into secondary recipients, Whereas animals that received bone marrow from untreated animals reconstituted with 2%transduced cells, animals receiving marrow from 6-BG/BCNU-treated animals reconstituted with 94% transduced cells, demonstrating nearly complete selection for stem cells in the primary animals. Mice reconstituted with marrowfrom animals treated with BCNU only demonstrated 23% transduced cells, consistent with partial selection of stem cells in the primary mice. The levels of transduced cells also correlated with survival during a second round of intensive combination chemotherapy (probability of survival: 6-BG/BCNU, 1.0; BCNU alone, >0.70; no treatment, <0.1). These data demonstrate that mutant MGMT expressed in the bone marrow can protect mice from time- and dose-intensive chemotherapy and that the combination of 6-BG and BCNU leads to uniform selection of transduced stem cells in vivo in mice.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 27/09/20 alle ore 20:58:44