2010 Fiscal Year Final Research Report
Effects of functional ABCG2 polymorphisms on the sensitivities/adverse effects of gefitinib in patients with non-small-cell lung cancer
| Project/Area Number |
20590372
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Human pathology
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| Research Institution | Dokkyo Medical University |
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Principal Investigator |
IMAI Yasuo Dokkyo Medical University, 医学部, 准教授 (10342651)
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| Co-Investigator(Renkei-kenkyūsha) |
UEDA Yoshihiko 獨協医科大学, 医学部, 教授 (50151808)
UEDA Yoshihiko 獨協医科大学, 医学部, 助教 (50364542)
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| Project Period (FY) |
2008 – 2010
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| Keywords | 分子病理 / 抗癌剤感受性・副作用発症予測 / 遺伝子診断 |
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| Research Abstract |
ABCG2 is a half-size ATP-binding cassette transporter implicated in cellular gefitinib transport. Reportedly, the C421A ABCG2 gene variant was associated with gefitinib-induced diarrhea in Caucasian patients with non-small cell lung cancer. C421A ABCG2, resulting in Q141K substitution, is more prevalent in Asian populations. Therefore, the putative relationship between gefitinib-induced adverse effects and this functional polymorphism was investigated in 75 Japanese patients with non-small cell lung cancer treated with gefitinib 250 mg/d orally. C376T, resulting in truncated, non-functional ABCG2, was also investigated. Forty one (54.7%) patients harbored 376T or 421A ABCG2 on at least one allele, while the remaining 34 (45.3%) were wild type for ABCG2. No significant group differences were observed in frequency of gefitinib-related diarrhea or other adverse effects. Next, DLD-1 colon cancer cells expressing wild-type (DLD-1/WT) or 141K mutant ABCG2 (DLD-1/Q141K) were established for investigation of in-vitro cell sensitivity to the ABCG2-substrate drugs, gefitinib and SN-38. ABCG2 expression was much lower in DLD-1/Q141K cells than in DLD-1/WT cells, despite similar ABCG2 mRNA levels. DLD-1/WT cells acquired more resistance to SN-38 than did DLD-1/Q141K cells, but neither cell line acquired gefitinib resistance compared with parental cells. In-vitro data also suggested that ABCG2 has only a limited role in toxicity of gefitinib, but not SN-38, in colon-derived cells.
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Research Products
(6 results)
