Rescue me: Why chemotherapy fails and what do we do when it does (Proceedings)

Many pets have successfully achieved remission, or more accurately "disease free intervals" with any number of chemotherapy protocols. But what happens when treatments fail or a patient cannot tolerate a standard therapy regimen? The unique way any cancer patient is treated depends on several factors: stage of disease, paraneoplastic syndromes if any, the patient's general health status, and the owner's commitment to therapy including cost of treatment, time involved, and understanding of all potential side effects. Left untreated, patients will most likely succumb to their disease rapidly.

Lymphoma is a systemic disease and thus requires treatment that will address this issue if long term survival is to be achieved. Despite the great wealth of chemotherapy protocols in use today, we remain unable to routinely and substantially move beyond the published remission times of 12 months, regardless of the drug combinations that are used. One largely confounding factor is multi-drug resistance. That cells have the ability to transport molecules out of cytoplasm is not a new finding. Membrane transporters or "pumps" were exhibited in a laboratory setting in the 1970's and showed a protein, P-glycoprotein, was involved with drug resistance in several cell lines. The gene for P-glycoprotein was called MDR-1. It would seem that the straightest path to correct multi-drug resistance would be one whereby MDR-1 was rendered unable to "protect" cancer cells. However, this thinking does not allow for those non-cancerous cells (ie. bone marrow) that are also affected by chemotherapeutics. Dogs with a mutation in the MDR-1 gene or "sensitive" patients lack the ability to produce a protein necessary to block a number of drugs from crossing the blood- brain barrier and, thus accumulate at levels that become toxic. Targeted therapies are new approaches that strive to overcome this conundrum.

Melanoma is another malignancy that poses a distinctive set of challenges. While rare in the cat, it can occur in both the canine and feline patient. Malignant melanoma is, in fact, the most common oral tumor found in dogs. While local disease responds either alone or in combination to surgery, radiation, and or chemotherapy, almost all patients are lost to distant disease. Novel therapy such as the "melanoma vaccine" has added a new weapon in the fight against metastasis. A therapeutic vaccine, this treatment is currently approved for conditional use in a specific subset of canine patients.

Tyrosine-kinase inhibitors are another promising new therapy on the horizon for mast cell tumors. This group of drugs acts upon the area of cells that control cellular proliferation and differentiation. Overexpression of tyrosine kinase proteins or genetic mutation can lead to cancerous cell growth. There are several different kinases in a variety of families. C-Kit is only one. Research into inhibition mechanisms remains ongoing and the body of knowledge is continuously updated with new findings.