Mechanisms of drug resistance in veterinary oncology – A review with an emphasis on canine lymphoma

Abstract

Drug resistance (DR) is the major limiting factor in the successful treatment of systemic neoplasia with cytotoxic chemotherapy. DR can be either intrinsic or acquired, and although the development and clinical implications are different, the underlying mechanisms are likely to be similar. Most causes for DR are pharmacodynamic in nature, result from adaptations within the tumor cell and include reduced drug uptake, increased drug efflux, changes in drug metabolism or drug target, increased capacity to repair druginduced DNA damage or increased resistance to apoptosis. The role of active drug efflux transporters, and those of the ABCtransporter family in particular, have been studied extensively in human oncology and to a lesser extent in veterinary medicine. Methods reported to assess ABCtransporter status include detection of the actual protein (Western blot, immunohistochemistry), mRNA or ABCtransporter function. The three major ABCtransporters associated with DR in human oncology are ABCB1 or Pgp, ABCC1 or MRP1, and ABCG2 or BCRP, and have been demonstrated in canine cell lines, healthy dogs and dogs with cancer. Although this supports a causative role for these ABCtransporters in DR cytotoxic agents in the dog, the relative contribution to the clinical phenotype of DR in canine cancer remains an area of debate and requires further prospective studies