Studies on the relation between drug sensitivity and transporters in cancer for tailor-made cancer chemotherapy

肿瘤化疗中药物敏感性与转运蛋白关系的研究

• 批准号: 15590127
• 负责人: MIYAMOTO Ken-ichi
• 金额: $ 1.92万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590127/
• 关键词: Tailor-made chemotherapy; Transporter; in vivo drug resistance; MRP2; Cisplatin; Bilirubin; Renal cell carcinoma; Hepatocellular carcinoma; n vitro感受性試験; in vivo抗癌剤耐性; in vitro薬剤感受性試験

In this study, we revealed the "in vivo drug resistance" in hepatocellular carcinomas and renal cell carcinoma. The cancer cells are resistant to cicplatin only in proliferating in the host, but when they were incubated in vitro, the drug sensitivity is markedly increased. We clarified the mechanisms of the in vivo drug resistance. The cells express several ABC transporters on the plasma membrane, and the expression of MRP2 among transporters was disappeared during in vitro culture and was incresed by addition of conjugated bilirubin. These results strongly suggest when cancer cells are growing in the host, MRP2 induced by bilirubin extrude anticancer drugs including cisplatin and the cancer cells are resistant to the anticancer drugs. On the other hand, the expression level of MRP2 was quite different among cancer specimens from patients. Therefore, estimation of the transporter expression level of cancer biopsy specimens may be very useful for cancer chemotherapy and become the tailor-made chemotherapy.

在这项研究中，我们揭示了肝细胞癌和肾癌的体内耐药。癌细胞只有在宿主体内增殖时才对顺铂耐药，但当它们在体外孵育时，药物敏感性显著增加。阐明了体内耐药的机制。细胞在细胞膜上表达多种ABC转运蛋白，在体外培养过程中，转运蛋白MRP2的表达消失，加入结合胆红素后，MRP2表达增强。这些结果强烈提示，当癌细胞在宿主体内生长时，胆红素诱导的MRP2分泌包括顺铂在内的抗癌药物，癌细胞对抗癌药物具有耐药性。另一方面，MRP2的表达水平在不同患者的癌组织中差异很大。因此，估计肿瘤活检标本转运蛋白的表达水平可能对肿瘤化疗非常有用，并可能成为量身定制的化疗方案。

项目成果

Influence of cytarabine and cyclophosphamide to disposition kinetics of cyclosporin A on bone marrow transplantation.

阿糖胞苷和环磷酰胺对环孢素A在骨髓移植中的处置动力学的影响。

• 发表时间: 2003
• 期刊: Transplant. Int. 16
• 作者: Pan;X.et al.;Tsutomu Shimada他6名
• 通讯作者: Tsutomu Shimada他6名

Disposition kinetics of taxanes after intraperitoneal administration in rats and influence of surfactant vehicles.

大鼠腹腔给药后紫杉烷类药物的处置动力学及表面活性剂载体的影响。

• 发表时间: 2004
• 期刊: J.Pharm.Pharmacol. 56
• 作者: Horiba;N. et al.;Akemi Shimizu et al.;Koichi Yokogawa他10名
• 通讯作者: Koichi Yokogawa他10名

Reversal of P-glycoprotein-dependent resistance to vinblastine by newly synthesized bisbenzylisoquinoline alkaloids in mouse leukemia P388 cells.

• DOI: 10.1248/bpb.28.1979
• 发表时间: 2005-10
• 期刊: Biological & pharmaceutical bulletin
• 影响因子: 2
• 作者: Feng-peng Wang;Li Wang;Jin-song Yang;M. Nomura;K. Miyamoto

Effect of intraperitoneal administration of docetaxel on peritoneal dissemination of gastric cancer.

腹腔注射多西紫杉醇对胃癌腹膜播散的影响。

• DOI: 10.1016/j.canlet.2004.03.018
• 发表时间: 2004
• 期刊: Cancer letters
• 影响因子: 9.7
• 作者: Y. Yonemura;Y. Endou;E. Bando;K. Kuno;T. Kawamura;M. Kimura;T. Shimada;K. Miyamoto;Takuma Sasaki;P. Sugarbaker
• 通讯作者: P. Sugarbaker

Long-term levothyroxine decreases the oral bioavailability of cyclosporin A by inducing P-glycoprotein in small intestine.

长期左旋甲状腺素通过诱导小肠中的 P-糖蛋白降低环孢菌素 A 的口服生物利用度。

• 发表时间: 2005
• 期刊: Drug Metab. Pharmacokin. 20・5
• 作者: Urakami;Y. et al.;Mingji Jin他5名
• 通讯作者: Mingji Jin他5名