Chemoprotective gene transfer II: multilineage in vivo protection of haemopoiesis against the effects of an antitumour agent by expression of a mutant human O6-alkylguanine-DNA alkyltransferase.

2.50
Hdl Handle:
http://hdl.handle.net/10541/92044
Title:
Chemoprotective gene transfer II: multilineage in vivo protection of haemopoiesis against the effects of an antitumour agent by expression of a mutant human O6-alkylguanine-DNA alkyltransferase.
Authors:
Chinnasamy, Nachimuthu; Rafferty, Joseph A; Hickson, Ian; Lashford, Linda S; Longhurst, S J; Thatcher, Nick; Margison, Geoffrey P; Dexter, T Michael; Fairbairn, Leslie J
Abstract:
Murine bone marrow cells were transduced ex vivo with a retrovirus encoding an O6-benzylguanine (O6-beG) insensitive, double mutant form of the human DNA repair protein O6-alkylguanine-DNA alkyltransferase (hATPA/GA). In animals reconstituted with the transduced bone marrow, about 50% of cells in the multipotent spleen colony-forming cells (CFU-S) and lineage restricted granulocyte-macrophage (GM-CFC) haemopoietic progenitor populations were found to be carrying the transgene and this correlated with the frequency of bone marrow cells and spleen colonies which stained positive for hATPA/GA by immunocyto-chemistry. Expression of hATPA/GA was associated with significant in vivo protection of both CFU-S (P = 0.001) and GM-CFC (P < 0.024) against the toxicity of the antitumour methylating agent, temozolomide, given in combination with O6-beG. Expression of hATPA/GA also led to a reduction in the frequency of combined O6-beG/temozolomide-induced micronuclei seen in polychromatic erythrocytes (P < 0.003). This study is the first to demonstrate in vivo protection of multipotent haemopoietic progenitors against the toxic and clastogenic effects of an O6-alkylating agent in the presence of O6-beG. It also represents the first report of reduced clastogenesis as a consequence of expression of an O6-beG-resistant ATase. In the accompanying article we report hATPA/GA-mediated resistance of human CD34+ haemopoietic progenitors to combined O6-beG/O6-alkylating agent toxicity. Together these two reports suggest that a gene therapy strategy whereby protection of normal haemopoietic tissue may be combined with O6-beG-mediated tumour sensitisation may be efficacious in achieving an increase in therapeutic index.
Affiliation:
CRC Sections of Genome Damage and Repair, Paterson Institute for Cancer Research, Manchester, UK.
Citation:
Chemoprotective gene transfer II: multilineage in vivo protection of haemopoiesis against the effects of an antitumour agent by expression of a mutant human O6-alkylguanine-DNA alkyltransferase. 1998, 5 (6):842-7 Gene Ther.
Journal:
Gene Therapy
Issue Date:
Jun-1998
URI:
http://hdl.handle.net/10541/92044
DOI:
10.1038/sj.gt.3300699
PubMed ID:
9747465
Type:
Article
Language:
en
ISSN:
0969-7128
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorChinnasamy, Nachimuthuen
dc.contributor.authorRafferty, Joseph Aen
dc.contributor.authorHickson, Ianen
dc.contributor.authorLashford, Linda Sen
dc.contributor.authorLonghurst, S Jen
dc.contributor.authorThatcher, Nicken
dc.contributor.authorMargison, Geoffrey Pen
dc.contributor.authorDexter, T Michaelen
dc.contributor.authorFairbairn, Leslie Jen
dc.date.accessioned2010-02-12T16:29:55Z-
dc.date.available2010-02-12T16:29:55Z-
dc.date.issued1998-06-
dc.identifier.citationChemoprotective gene transfer II: multilineage in vivo protection of haemopoiesis against the effects of an antitumour agent by expression of a mutant human O6-alkylguanine-DNA alkyltransferase. 1998, 5 (6):842-7 Gene Ther.en
dc.identifier.issn0969-7128-
dc.identifier.pmid9747465-
dc.identifier.doi10.1038/sj.gt.3300699-
dc.identifier.urihttp://hdl.handle.net/10541/92044-
dc.description.abstractMurine bone marrow cells were transduced ex vivo with a retrovirus encoding an O6-benzylguanine (O6-beG) insensitive, double mutant form of the human DNA repair protein O6-alkylguanine-DNA alkyltransferase (hATPA/GA). In animals reconstituted with the transduced bone marrow, about 50% of cells in the multipotent spleen colony-forming cells (CFU-S) and lineage restricted granulocyte-macrophage (GM-CFC) haemopoietic progenitor populations were found to be carrying the transgene and this correlated with the frequency of bone marrow cells and spleen colonies which stained positive for hATPA/GA by immunocyto-chemistry. Expression of hATPA/GA was associated with significant in vivo protection of both CFU-S (P = 0.001) and GM-CFC (P < 0.024) against the toxicity of the antitumour methylating agent, temozolomide, given in combination with O6-beG. Expression of hATPA/GA also led to a reduction in the frequency of combined O6-beG/temozolomide-induced micronuclei seen in polychromatic erythrocytes (P < 0.003). This study is the first to demonstrate in vivo protection of multipotent haemopoietic progenitors against the toxic and clastogenic effects of an O6-alkylating agent in the presence of O6-beG. It also represents the first report of reduced clastogenesis as a consequence of expression of an O6-beG-resistant ATase. In the accompanying article we report hATPA/GA-mediated resistance of human CD34+ haemopoietic progenitors to combined O6-beG/O6-alkylating agent toxicity. Together these two reports suggest that a gene therapy strategy whereby protection of normal haemopoietic tissue may be combined with O6-beG-mediated tumour sensitisation may be efficacious in achieving an increase in therapeutic index.en
dc.language.isoenen
dc.subject.meshAnimals-
dc.subject.meshAntineoplastic Agents, Alkylating-
dc.subject.meshBone Marrow Cells-
dc.subject.meshCell Survival-
dc.subject.meshDacarbazine-
dc.subject.meshGene Expression-
dc.subject.meshGene Transfer Techniques-
dc.subject.meshGenetic Vectors-
dc.subject.meshMale-
dc.subject.meshMice-
dc.subject.meshMice, Inbred Strains-
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase-
dc.subject.meshPolymerase Chain Reaction-
dc.subject.meshRetroviridae-
dc.subject.meshSpleen-
dc.subject.meshStem Cells-
dc.titleChemoprotective gene transfer II: multilineage in vivo protection of haemopoiesis against the effects of an antitumour agent by expression of a mutant human O6-alkylguanine-DNA alkyltransferase.en
dc.typeArticleen
dc.contributor.departmentCRC Sections of Genome Damage and Repair, Paterson Institute for Cancer Research, Manchester, UK.en
dc.identifier.journalGene Therapyen

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