P-Glycoprotein Activity at Diagnosis Does Not Predict Therapy Outcome and Survival in Canine B-Cell Lymphoma

SIMPLE SUMMARY: Clinical experience in human and canine clinics shows that following initial response to treatment, drug-resistant cancer cells frequently evolve and eventually, most tumors become resistant to all available therapies. The most straightforward cause of therapy resistance is linked to cellular alterations that prevent drugs from acting on their target. Drug efflux mediated by the ABC transporter P-glycoprotein (P-gp) contributes to unfavorable treatment outcome in several human malignancies. Here, we characterize a large cohort of canine B-cell lymphoma patients followed for over 7 years. We show that the intrinsic P-gp activity of tumor cells characterized at the time of diagnosis is not predictive for therapy outcome. Our results highlight the complexity of clinical drug resistance mechanisms and suggests that the relevance of P-gp in acquired resistance should be further investigated by the continuous monitoring of tumor cells during treatment. ABSTRACT: Various mechanisms are known to be involved in the development of multidrug resistance during cancer treatment. P-glycoprotein (P-gp) decreases the intracellular concentrations of cytotoxic drugs by an energy-dependent efflux mechanism. The aim of this study was to investigate the predictive value of P-gp function based on the evaluation of P-gp activity in tumor cells obtained from canine B-cell lymphoma patients at diagnosis. P-gp function of 79 immunophenotyped canine lymphoma samples was determined by flow cytometry using the Calcein assay. Dogs were treated with either the CHOP or the L-CHOP protocol, a subset of relapsed patients received L-asparaginase and lomustine rescue treatments. Among the 79 dogs, the median overall survival time was 417 days, and the median relapse-free period was 301 days. 47 percent of the samples showed high P-gp activity, which was significantly higher in Stage IV cancer patients compared to Stage II + III and V. Whereas staging was associated with major differences in survival times, we found that the intrinsic P-gp activity of tumor cells measured at diagnosis is not predictive for therapy outcome. Further studies are needed to identify the intrinsic and acquired resistant mechanisms that shape therapy response and survival in B-cell canine lymphoma patients.