Enhancing hemopoietic drug resistance: a rationale for reconsidering the clinical use of mitozolomide.

2.50
Hdl Handle:
http://hdl.handle.net/10541/86691
Title:
Enhancing hemopoietic drug resistance: a rationale for reconsidering the clinical use of mitozolomide.
Authors:
Fairbairn, Leslie J; Chinnasamy, Nachimuthu; Lashford, Linda S; Chinnasamy, Dhanalakshmi; Rafferty, Joseph A
Abstract:
Retroviral gene transfer was used to achieve expression in mouse bone marrow of a mutant form of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (hATPA/GA), which exhibits resistance to inactivation by O6-benzylguanine (O6-beG). After reconstitution of mice with transduced bone marrow, approximately 50% of the bipotent granulocyte-macrophage colony-forming cell (GM-CFC) and multipotent spleen colony-forming unit (CFU-S) hemopoietic populations showed expression of the transgene; this expression was associated with resistance to either mitozolomide or to a combination of O6-beG and mitozolomide, relative to mock-transduced controls. Thus, at a dose of mitozolomide in vivo that allowed only 70% and 62% survival of mock-transduced GM-CFC and CFU-S, respectively, the hATPA/GA CFC were totally resistant to the same dose of mitozolomide (P < .05 and .001, respectively). In the presence of O6-beG, the toxicity of mitozolomide was greatly potentiated. Only 24% and 18%, respectively, of mock-transduced GM-CFC and CFU-S survived combination treatment, whereas 45% (P < .05) and 37% (P < .01) of GM-CFC and CFU-S, respectively, from hATPA/GA mice survived the same combination of doses. Furthermore, as a result of transgene expression, the number of micronucleated polychromatic erythrocytes induced by mitozolomide was significantly reduced (P < .05) by 40% relative to mock-transduced controls, indicating the potential of this approach to reduce the frequency of mutation associated with chemotherapy exposure. The protection against the toxic and clastogenic effects of mitozolomide in both primitive and more mature hemopoietic cells suggests that the severe myelosuppression that halted further clinical investigation of this drug could be substantially ameliorated by the exogenous expression of O6-alkylguanine-DNA alkyltransferase. Therefore, these data raise the prospect for the reinvestigation of mitozolomide and other proscribed drugs in the context of genetically protected hemopoiesis.
Affiliation:
Cancer Research Campaign Sections of Hemopoietic Cell and Gene Therapeutics, Paterson Institute for Cancer Research, Manchester, United Kingdom.
Citation:
Enhancing hemopoietic drug resistance: a rationale for reconsidering the clinical use of mitozolomide. 2000, 7 (2):233-9 Cancer Gene Ther.
Journal:
Cancer Gene Therapy
Issue Date:
Feb-2000
URI:
http://hdl.handle.net/10541/86691
DOI:
10.1038/sj.cgt.7700120
PubMed ID:
10770631
Type:
Article
Language:
en
ISSN:
0929-1903
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorFairbairn, Leslie Jen
dc.contributor.authorChinnasamy, Nachimuthuen
dc.contributor.authorLashford, Linda Sen
dc.contributor.authorChinnasamy, Dhanalakshmien
dc.contributor.authorRafferty, Joseph Aen
dc.date.accessioned2009-11-23T12:10:59Z-
dc.date.available2009-11-23T12:10:59Z-
dc.date.issued2000-02-
dc.identifier.citationEnhancing hemopoietic drug resistance: a rationale for reconsidering the clinical use of mitozolomide. 2000, 7 (2):233-9 Cancer Gene Ther.en
dc.identifier.issn0929-1903-
dc.identifier.pmid10770631-
dc.identifier.doi10.1038/sj.cgt.7700120-
dc.identifier.urihttp://hdl.handle.net/10541/86691-
dc.description.abstractRetroviral gene transfer was used to achieve expression in mouse bone marrow of a mutant form of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (hATPA/GA), which exhibits resistance to inactivation by O6-benzylguanine (O6-beG). After reconstitution of mice with transduced bone marrow, approximately 50% of the bipotent granulocyte-macrophage colony-forming cell (GM-CFC) and multipotent spleen colony-forming unit (CFU-S) hemopoietic populations showed expression of the transgene; this expression was associated with resistance to either mitozolomide or to a combination of O6-beG and mitozolomide, relative to mock-transduced controls. Thus, at a dose of mitozolomide in vivo that allowed only 70% and 62% survival of mock-transduced GM-CFC and CFU-S, respectively, the hATPA/GA CFC were totally resistant to the same dose of mitozolomide (P < .05 and .001, respectively). In the presence of O6-beG, the toxicity of mitozolomide was greatly potentiated. Only 24% and 18%, respectively, of mock-transduced GM-CFC and CFU-S survived combination treatment, whereas 45% (P < .05) and 37% (P < .01) of GM-CFC and CFU-S, respectively, from hATPA/GA mice survived the same combination of doses. Furthermore, as a result of transgene expression, the number of micronucleated polychromatic erythrocytes induced by mitozolomide was significantly reduced (P < .05) by 40% relative to mock-transduced controls, indicating the potential of this approach to reduce the frequency of mutation associated with chemotherapy exposure. The protection against the toxic and clastogenic effects of mitozolomide in both primitive and more mature hemopoietic cells suggests that the severe myelosuppression that halted further clinical investigation of this drug could be substantially ameliorated by the exogenous expression of O6-alkylguanine-DNA alkyltransferase. Therefore, these data raise the prospect for the reinvestigation of mitozolomide and other proscribed drugs in the context of genetically protected hemopoiesis.en
dc.language.isoenen
dc.subjectCancer Drug Resistanceen
dc.subjectHaematopoietic Stem Cellsen
dc.subject.meshAnimals-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshBone Marrow Cells-
dc.subject.meshBone Marrow Transplantation-
dc.subject.meshColony-Forming Units Assay-
dc.subject.meshDrug Resistance, Neoplasm-
dc.subject.meshDrug Synergism-
dc.subject.meshGene Transfer Techniques-
dc.subject.meshHematopoietic Stem Cells-
dc.subject.meshMale-
dc.subject.meshMice-
dc.subject.meshMice, Inbred C57BL-
dc.subject.meshMice, Inbred DBA-
dc.subject.meshMutagens-
dc.subject.meshNitrogen Mustard Compounds-
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase-
dc.subject.meshRetroviridae-
dc.titleEnhancing hemopoietic drug resistance: a rationale for reconsidering the clinical use of mitozolomide.en
dc.typeArticleen
dc.contributor.departmentCancer Research Campaign Sections of Hemopoietic Cell and Gene Therapeutics, Paterson Institute for Cancer Research, Manchester, United Kingdom.en
dc.identifier.journalCancer Gene Therapyen

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