Ito Daisuke, Childress Michael, Mason Nicola, Winter Amber, O'Brien Timothy, Henson Michael, Borgatti Antonella, Lewellen Mitzi, Krick Erika, Stewart Jane, Lahrman Sarah, Rajwa Bartek, Scott Milcah C, Seelig Davis, Koopmeiners Joseph, Ruetz Stephan, Modiano Jaime
Animal Cancer Care and Research Program, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, 55108, USA.
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, 55108, USA.
F1000Res. 2015 Feb 11;4:42. doi: 10.12688/f1000research.6055.3. eCollection 2015.
We previously described a population of lymphoid progenitor cells (LPCs) in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and "slow proliferation" molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP binding cassette B1 transporter (ABCB1, a.k.a., p-glycoprotein/multidrug resistance protein-1) used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy naïve large B-cell lymphoma. Twenty dogs were enrolled into a double-blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg) or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1 cells does not alter the composition of lymph node or blood LPCs, and it does not appear to be sufficient to prolong doxorubicin-dependent remissions in this setting.
我们之前描述过犬B细胞淋巴瘤中的一群淋巴样祖细胞（LPC），其特征为保留早期祖细胞标志物CD34和CD117以及在异种移植环境中持续存在的“缓慢增殖”分子特征。我们研究了在新辅助治疗中使用的ATP结合盒转运体B1（ABCB1，又名P-糖蛋白/多药耐药蛋白-1）选择性抑制剂valspodar是否会使LPC对多柔比星敏感，并延长初治大B细胞淋巴瘤犬的缓解期。20只犬被纳入一项双盲、安慰剂对照研究，试验组和对照组分别每日口服valspodar（7.5mg/kg）或安慰剂两次，持续5天，随后每21天进行5次多柔比星治疗，首次剂量降低以减轻ABCB1抑制的潜在副作用。在诊断时、新辅助治疗期第4天以及首次化疗剂量后1周对淋巴结和血液中的LPC进行定量。Valspodar治疗耐受性良好。两组在淋巴结或外周血中总的LPC数量、无事件生存期或总生存期方面均无差异。总体而言，我们得出结论，valspodar在犬B细胞淋巴瘤的新辅助治疗中可以安全给药；然而，其用于减弱ABCB1细胞的作用并不会改变淋巴结或血液中LPC的组成，并且在这种情况下似乎不足以延长依赖多柔比星的缓解期。
