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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.
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
html.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.


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