| Project/Area Number |
20791557
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Surgical dentistry
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| Research Institution | Matsumoto Dental University |
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Principal Investigator |
DOTO Ryosuke Matsumoto Dental University, 歯学部, 助教 (40329470)
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| Project Period (FY) |
2008 – 2009
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| Project Status |
Completed (Fiscal Year 2009)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2008: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
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| Keywords | ABC transporter / MDR1 / MRP1 / GST / 抗癌剤多剤耐性 / 薬剤排泄機構 / MDRl / MRPl |
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| Research Abstract |
Objectives : The poor clinical response of salivary gland adenocarcinoma (SGA) to combined chemotherapy for head-and-neck cancer (HNC) suggests that the sensitivities and/or mechanisms of resistance to anti-cancer drugs differ between SGA and oral squamous cell carcinoma (SCC). The present study aimed to clarify whether expression of the ATP-binding cassette (ABC) transporters MDR1 and MRP1 is associated with multidrug resistance (MDR) in HNC, and to determine differences in the associated processes between SGA and SCC.
Materials and Methods: The expression of ABC transporters and glutathione S-transferase enzymes was studied immunohistochemically in the normal salivary gland and in cancer tissues from patients. Expression of MDR1 and MRP1 was analyzed using Western blotting in both SGA and SCC cell lines following vincristine administration. We also determined mdr1 and mrp1 mRNA expression levels using reverse transcriptase-polymerase chain reaction (RT-PCR).
Results : Immunohistochemical analysis revealed MDR1 and MRP1 expression in ductal cells of salivary glands, but not in the oral mucosal epithelium. When compared with SCC, SGA displayed expressed more intense MRP1 and more MDR1. Analysis in vitro indicated more MDR1, MRP1 and glutathione S-transferase (GST)-pi class enzyme expression in drug-resistant SGA cells than in parental SGA or drug-resistant and drug-sensitive SCC cell lines. Immunoblotting and PCR confirmed that the expression of GST-pi was increased relative to that of MRP1 in drug-resistant SGA cells. The MDR1 inhibitor verapamil obviously enhanced cytotoxicity in resistant SGA and SCC cells at low vincristine concentrations. The GST inhibitor curcumin also enhanced cytotoxicity, particularly in resistant SGA cells after the MDR1 efflux barrier had been reversed by verapamil.
Conclusion : These results indicate that MRP1/GST-pi enzymes are involved in the acquired-resistance phenotype of SGA.
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