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年里，有大量针对犬淋巴肿瘤的治疗临床试验的报道；然而，目前的研究并未取得明显的改善，旨在开发新的治疗策略。基于肿瘤细胞的分子分析。关于肿瘤细胞的耐药性，检查了药物外流泵、药物代谢分子、细胞周期调节分子和凋亡相关分子的表达增加。 P-糖蛋白在狗的耐药性淋巴肿瘤中发现了药物外排泵之一的p53基因（P-gp）和编码细胞周期/凋亡相关分子的p53基因突变。接下来，我们建立了一个检测系统来量化p53基因的拷贝数。该检测系统能够对化疗后的少量残留肿瘤细胞进行定量，即即使在诱导后也可以检测到微小残留病（MRD）。化疗结束时MRD的量与复发前的缓解持续时间呈负相关，这些结果表明MRD可以作为比较不同化疗药物疗效的客观标志物。此外，本研究引入了基于每个阶段/患者的 MRD 水平的定制治疗。因为狗的淋巴肿瘤可以被认为是该疾病的动物模型。人类疾病，本研究为开发人类淋巴肿瘤的新治疗策略提供了有用的信息。

项目成果

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
• 作者: Fujino; Y.; et al.
• 通讯作者: et al.

Long term survival of primary skeletal muscle lymphoma in a Miniature dachshund

小型腊肠犬原发性骨骼肌淋巴瘤的长期存活

• 发表时间: 2010
• 作者: Takeuchi; Y.; 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、奎尼丁和洛哌丁胺血浆浓度的适度影响

• 发表时间: 2008
• 作者: Kitamura; Y.; 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(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
• 作者: Matsuura; S.; et al.
• 通讯作者: et al.

Detection of centrosome amplification as a surrogate marker of dysfunction in p53 pathway-p53 gene mutation or MDM2 overexpression.

检测中心体扩增作为 p53 通路 -p53 基因突变或 MDM2 过表达功能障碍的替代标记。

• 发表时间: 2005
• 作者: Kaneko; N; et al.
• 通讯作者: et al.