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 drug-induced DNA damage or increased resistance to apoptosis. The role of active drug efflux transporters, and those of the ABC-transporter family in particular, have been studied extensively in human oncology and to a lesser extent in veterinary medicine. Methods reported to assess ABC-transporter status include detection of the actual protein (Western blot, immunohistochemistry), mRNA or ABC-transporter function. The three major ABC-transporters associated with DR in human oncology are ABCB1 or P-gp, 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 ABC-transporters 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.

Keywords: BCRP; MRP1; P‐gp; cancer; chemotherapy; dog; multi‐drug resistance; non‐Hodgkin; therapy.

Figure 1

The major cellular drug resistance mechanisms.

Figure 2

Overlap in cytotoxic dugs as substrates for the major ABC-transporters ABCB1 (P-gp), ABCC1 (MRP1) and ABCG2 (BCRP).