Abstract
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.
Highlights
The importance of tumor-propagating cells in the pathogenesis of cancer is becoming increasingly well recognized[1]
Our group identified a subset of lymphoid progenitor cells (LPCs) in primary canine B-cell lymphomas that were characterized by co-expression of hematopoietic progenitor antigens CD34, CD117, and CD133, the B-lymphoid lineage marker CD22, and the common leukocyte antigen CD456
The effect of valspodar was comparable to that observed in verapamil (Figure 2, Dataset a), which inhibits both ABCB1 and ABCG2 at the 50–100 μM concentrations used in this assay
Summary
The importance of tumor-propagating cells in the pathogenesis of cancer is becoming increasingly well recognized[1]. Our group identified a subset of lymphoid progenitor cells (LPCs) in primary canine B-cell lymphomas that were characterized by co-expression of hematopoietic progenitor antigens CD34, CD117, and CD133, the B-lymphoid lineage marker CD22, and the common leukocyte antigen CD456 These LPCs had phenotypic properties consistent with tumor-initiating or tumor-propagating cells (TIC/TPC); they persisted in the xenotransplantation setting, suggesting that they were relevant to the biology of this disease in vivo[6]. When compared with the bulk of the tumor cells, LPCs showed significantly lower expression of 44 genes across the genome, mapping to cell cycle and transmembrane signaling pathways[7] This indicated that LPCs exhibit the characteristic “slow proliferation” seen in normal bone marrow-derived hematopoietic stem cells and in TIC/TPC in other cancers
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
