A longitudinal study of ABC transporter expression in canine multicentric lymphoma

Abstract

Canine lymphoma is typically treated with a doxorubicin-based multidrug chemotherapy protocol. Although this is often initially successful, tumour recurrence is common and frequently refractory to treatment. Failure to respond to chemotherapy is thought to represent drug resistance and has been associated with active efflux of cytostatic drugs by transporter proteins of the ATP-binding cassette (ABC) family, including P-glycoprotein (ABCB1), MRP1 (ABCC1) and BCRP (ABCG2). In this study, ABC transporter mRNA expression was assessed in 63 dogs diagnosed with multicentric lymphoma that were treated with a doxorubicin-based chemotherapy protocol. Expression of ABCB1, ABCB5, ABCB8, ABCC1, ABCC3, ABCC5 and ABCG2 mRNA was quantified in tumour samples (n = 107) obtained at the time of diagnosis, at first tumour relapse and when the tumour was no longer responsive to cytostatic drugs while receiving chemotherapy. Expression data were related to patient demographics, staging, treatment response and drug resistance (absent, intrinsic, acquired). ABC transporter expression was independent of sex, weight, age, stage or substage, but T cell lymphoma and hypercalcaemia were associated with increased ABCB5 and ABCC5 expression, and decreased ABCC1 mRNA expression. Drug resistance occurred in 35/63 (55.6%) dogs and was associated with increased ABCB1 mRNA expression in a subset of dogs with B cell lymphoma, and with increased ABCG2 and decreased ABCB8, ABCC1 and ABCC3 mRNA expression in T cell lymphomas. ABC transporter expression in the pre-treatment sample was not predictive of the length of the first disease-free period or overall survival. Glucocorticoids had no effect on ABC transporter mRNA expression. In conclusion, drug resistance in canine multicentric lymphoma is an important cause of treatment failure and is associated with upregulation of ABCB1 and ABCG2 mRNA.