| Co-Investigator(Kenkyū-buntansha) |
YAMAZAKI Hitoshi Tokai University, School of Medicine, Assistant Professor, 医学部, 講師 (20191273)
TAMAOKI Norikazu Tokai University, School of Medicine, Professor, 医学部, 教授 (50055860)
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| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1995: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1994: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Research Abstract |
We examined whether the increased expression of P-glycoprotein (P-Gp) encoded by the human multidrug resistance gene MDR1 is related to acquired multidrug resistance of lung cancer in vivo. The lung cancer xenografts (LC-6, adenocarcinoma and Lu-24, small cell carcinoma) were initially sensitive to both vincristine (VCR,1.6 mg/kg : LC-6,45% ; Lu-24,39%) and doxorubicin (DOX,12mg/kg : LC-6,29% ; Lu-24,26%) by in vivo-chemosensitivity test. Resistant variants (LC-6R,66% and Lu-24R,68%) selected with VCR (0.4mg/kg, x 9) acquired cross-resistance to DOX (51%, and 55%, respectively) . The acquired resistance to VCR/DOX in LC-6R was circumvented by coadministration of cyclosporin A (CysA,35%/14%) . Reverse transcriptasepolymerase chain reaction assay showed increased levels of MDR1 expression in LC-6R and Lu-24R with stable MDR1 expression levels after 4 passages without VCR.P-Gp expression levels were elevated, and P-Gp positve tumor cells increased in both LC-6R and Lu-24R.These results su
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ggest that P-Gp/MDR1 overexpression is related to acquired multidrug resistance in lung cancer in vivo.
We examined the levels of expression of the multidrug resistance-associated protein (MRP) gene quantified by Northern blot analysis in comparison with those of the MDR1 gene determined by RT-PCR in 104 non-small cell lung (NSCLC) specimens (59 adenocarcinoma, Ad ; 40 squamous cell carcinoma, Sq ; 4 large cell carcinoma, La ; and 1 adenosquamous carcinoma, AdSq) . Thirty-three (31.7%) of the 104 NSCLC expressed the MRP gene at various levels. The NSCLC showing high levels of MRP gene expression (++, 19 of 33,57.6%) were predominantly squamous cell carcinomas (Ad 5, Sq 13, La 1) (p<0.05) . Six of the 8 NSCLC expressing high levels of MRP mRNA and no MDR1 (MRP++, MDR1-) were squamous cell carcinomas. Sixty-one of the 104 NSCLC patients received chemotherapy with MRP-related anticancer drugs (vindesine, VDS and etoposide, VP-16) . Twenty-three patients (37.7%) with tumor expressing high or moderate levels of MRP showed significantly worse prognoses than those with non or low-MRP-expressing tumours (p<0.05) . These results suggest that the level of MRP gene expression is related to the histopathology and prognosis of NSCLC. Less
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