Development of novel therapeutic strategies based on the molecular analyses of tumor cells in animal lymphomas

基于动物淋巴瘤肿瘤细胞的分子分析开发新的治疗策略

• 批准号: 17380186
• 负责人: TSUJIMOTO Hajime
• 金额: $ 10.18万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17380186/
• 关键词: dog; lymphoid tumor; lymphoma; chemotherapy; drug resistance; minimal residual disease; MRD; animal model; mdr1; p53; 予後; 分子病態; P-糖タンパク; p53遺伝子

For the past 30 years, a large number of therapeutic clinical trials for canine lymphoid tumors were reported; however, apparent improvement on the outcome of the patients has not been obtained. The present study was carried out to aim at the development of novel therapeutic strategies based upon the molecular analyses of the tumor cells.With respect to the drug resistance of the tumor cells, drug efflux pumps, drug metabolizing molecules, cell cycle-regulating molecules, and apoptosis-associated molecules were examined. The results indicated that increased expression of P-glycoprotein (P-gp), one of the drug efflux pump, and mutation of p53 gene encoding cell cycle/apoptosis-associated molecule were found in drug-resistant lymphoid tumors in dogs.Next, we established an assay system to quantify the copy number of rearranged immunoglobulin and T-cell receptor genes in lymphoid cells. The assay system enabled the quantification of a small number of residual tumor cells after chemotherapy, namely minimal residual disease (MRD). MRD could be detected in dogs even after induction of complete remission and gradually increased 1～2 months before relapse. The amount of MRD at the end of chemotherapy was negatively correlated with the remission duration until relapse. These findings indicated that the MRD could be an objective marker to compare the efficacy of different chemotherapeutic protocols and a negative prognostic factor for the relapse in canine lymphoma. Furthermore, the present study introduced a tailor-made therapy based on the MRD level in each phase/patient.Because the lymphoid tumors in dogs can be recognized as an animal model of the human disease, the present study provided useful information to develop novel therapeutic strategies in lymphoid tumors in humans.

在过去的30年中，据报道了大量的犬淋巴肿瘤的治疗临床试验。但是，尚未获得患者结果的明显改善。本研究的目的是基于肿瘤细胞的分子分析来开发新的治疗策略。与肿瘤细胞的耐药性，药物外排泵，药物代谢分子，细胞周期调节分子和凋亡相关的分子相关。结果表明，在狗狗中发现了一个分析的分析系统，在狗狗中发现了抗药性细胞，并在dogs中建立了contrangemogploblob的副本。化学疗法后，该测定系统能够定量少量残留肿瘤细胞，即残留疾病（MRD）。即使在诱导完全缓解后，也可以在狗中检测到MRD，并在缓解前逐渐增加1-2个月。化学疗法结束时的MRD量与缓解持续时间呈负相关。这些发现表明，MRD可能是比较不同化学治疗方案的有效性和对犬淋巴瘤缓解的负预后因素的有效性的客观标记。此外，本研究基于每个阶段/患者的MRD水平引入了量身定制的疗法。由于狗的淋巴样肿瘤可以被识别为人类疾病的动物模型，因此本研究提供了有用的信息来开发人类淋巴样肿瘤的新型治疗策略。

项目成果

Induction of chemoresistance in a canine cultured cell line by retroviral transduction of the canine multidrug resistance 1 gene(mdr1).

通过逆转录病毒转导犬多药耐药 1 基因 (mdr1) 在犬培养细胞系中诱导化疗耐药。

• 发表时间: 2007
• 期刊: Am. J. Vet. Res. 68
• 作者: Matsuura;S.;et al.
• 通讯作者: et al.

Molecular cytogenetic analysis of feline leukemia virus insertions in cat lymphoid tumor cells

猫淋巴肿瘤细胞中猫白血病病毒插入的分子细胞遗传学分析

• 发表时间: 2010
• 期刊: Journal of Virological Methods 163
• 作者: Fujino;Y.;et al.
• 通讯作者: et al.

A case of canine lymphomatoid granulomatosis with cutaneous lesions

犬淋巴瘤样肉芽肿病伴皮肤损害一例

• 发表时间: 2010
• 期刊: Journal of Veterinary Medical Science (In press)
• 作者: Shimazaki;T.;et al.
• 通讯作者: et al.

Induction of chemoresistance in a canine cultured cell line by retroviral transduction of the canine multidrug resistance 1 gene(mdr 1)

通过逆转录病毒转导犬多药耐药 1 基因 (mdr 1) 在犬培养细胞系中诱导化疗耐药

• 发表时间: 2007
• 期刊: American Journal of Veterinary Research 68
• 作者: Matsuura;S.;et al.
• 通讯作者: et al.

Modest effect of impaired P-glycoprotein on the plasma concentration of fexofenadine, quinidine, and loperamide following oral administration in collies.

受损的 P-糖蛋白对牧羊犬口服给药后非索非那定、奎尼丁和洛哌丁胺的血浆浓度有一定影响。

• 发表时间: 2008
• 期刊: Drug Metabolism and Disposition 36
• 作者: Kitamura;Y;et al.
• 通讯作者: et al.