Dual agent chemoprotection by retroviral co-expression of either MDR1 or MRP1 with the P140K mutant of O6-methylguanine-DNA-methyl transferase.

2.50
Hdl Handle:
http://hdl.handle.net/10541/72678
Title:
Dual agent chemoprotection by retroviral co-expression of either MDR1 or MRP1 with the P140K mutant of O6-methylguanine-DNA-methyl transferase.
Authors:
Southgate, Thomas D; Garside, Elloise; Margison, Geoffrey P; Fairbairn, Leslie J
Abstract:
Tumour resistance to chemotherapeutic agents results in most chemotherapy being administered in a multi-agent fashion that is often associated with a high level of toxicity in highly proliferative tissues such as the haematopoietic compartment. Thus, whilst many genetic manipulation strategies aim to protect normal tissue against a single component of a multi-agent regime, it is clearly preferable to protect normal cells against all toxicities. In this study we have used retroviral gene transfer to achieve co-expression of either p-glycoprotein (MDR1) or multi-drug resistance-related protein 1 (MRP1) with the P140K mutant form of O6-methylguanine-DNA-methyl transferase (MGMT) which, unlike the wild-type protein, is insensitive to inactivation by tumour sensitisers such as O6-benzylguanine (O6-BeG) or PaTrin2. The combination of certain MDR1/MRP1 substrate drugs with O6-alkylating agents (against which MGMT confers resistance) is particularly myelotoxic. We show here that haematopoietic progenitors co-expressing mutant MGMT with an ABC-transporter exhibit resistance to combination chemotherapy in vitro. This combination of drug transporter and DNA repair function may provide an effective in vivo protection of the haematopoietic compartment during tumour ablation using combination chemotherapy.
Affiliation:
Cancer Research UK Gene Therapy Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK. Tsouthgate@picr.man.ac.uk
Citation:
Dual agent chemoprotection by retroviral co-expression of either MDR1 or MRP1 with the P140K mutant of O6-methylguanine-DNA-methyl transferase. 2006, 8 (8):972-9 J Gene Med
Journal:
The Journal of Gene Medicine
Issue Date:
Aug-2006
URI:
http://hdl.handle.net/10541/72678
DOI:
10.1002/jgm.914
PubMed ID:
16733832
Type:
Article
Language:
en
ISSN:
1099-498X
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorSouthgate, Thomas D-
dc.contributor.authorGarside, Elloise-
dc.contributor.authorMargison, Geoffrey P-
dc.contributor.authorFairbairn, Leslie J-
dc.date.accessioned2009-07-07T10:01:47Z-
dc.date.available2009-07-07T10:01:47Z-
dc.date.issued2006-08-
dc.identifier.citationDual agent chemoprotection by retroviral co-expression of either MDR1 or MRP1 with the P140K mutant of O6-methylguanine-DNA-methyl transferase. 2006, 8 (8):972-9 J Gene Meden
dc.identifier.issn1099-498X-
dc.identifier.pmid16733832-
dc.identifier.doi10.1002/jgm.914-
dc.identifier.urihttp://hdl.handle.net/10541/72678-
dc.description.abstractTumour resistance to chemotherapeutic agents results in most chemotherapy being administered in a multi-agent fashion that is often associated with a high level of toxicity in highly proliferative tissues such as the haematopoietic compartment. Thus, whilst many genetic manipulation strategies aim to protect normal tissue against a single component of a multi-agent regime, it is clearly preferable to protect normal cells against all toxicities. In this study we have used retroviral gene transfer to achieve co-expression of either p-glycoprotein (MDR1) or multi-drug resistance-related protein 1 (MRP1) with the P140K mutant form of O6-methylguanine-DNA-methyl transferase (MGMT) which, unlike the wild-type protein, is insensitive to inactivation by tumour sensitisers such as O6-benzylguanine (O6-BeG) or PaTrin2. The combination of certain MDR1/MRP1 substrate drugs with O6-alkylating agents (against which MGMT confers resistance) is particularly myelotoxic. We show here that haematopoietic progenitors co-expressing mutant MGMT with an ABC-transporter exhibit resistance to combination chemotherapy in vitro. This combination of drug transporter and DNA repair function may provide an effective in vivo protection of the haematopoietic compartment during tumour ablation using combination chemotherapy.en
dc.language.isoenen
dc.subjectHaematopoietic Stem Cellsen
dc.subject.mesh3T3 Cells-
dc.subject.meshAnimals-
dc.subject.meshAntineoplastic Agents, Alkylating-
dc.subject.meshAntineoplastic Agents, Phytogenic-
dc.subject.meshAntineoplastic Combined Chemotherapy Protocols-
dc.subject.meshCarmustine-
dc.subject.meshDrug Resistance, Multiple-
dc.subject.meshDrug Resistance, Neoplasm-
dc.subject.meshEtoposide-
dc.subject.meshGene Expression-
dc.subject.meshGene Transfer Techniques-
dc.subject.meshGenes, MDR-
dc.subject.meshGreen Fluorescent Proteins-
dc.subject.meshHematopoietic Stem Cells-
dc.subject.meshHumans-
dc.subject.meshK562 Cells-
dc.subject.meshMice-
dc.subject.meshMultidrug Resistance-Associated Proteins-
dc.subject.meshMutation-
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase-
dc.subject.meshP-Glycoprotein-
dc.subject.meshRetroviridae-
dc.subject.meshTransduction, Genetic-
dc.titleDual agent chemoprotection by retroviral co-expression of either MDR1 or MRP1 with the P140K mutant of O6-methylguanine-DNA-methyl transferase.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK Gene Therapy Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK. Tsouthgate@picr.man.ac.uken
dc.identifier.journalThe Journal of Gene Medicineen

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