"Resistance to Chemotherapy" TUMOR TIDBITS, A BIWEEKLY VETERINARY ONCOLOGY E-LETTER Volume 2; Number 23; December 26, 2001. Editor: Kevin A. Hahn, DVM, PhD, Dipl - ACVIM (Oncology) & Overall Nice Guy! ANNOUNCEMENTS: Happy Holidays from the Doctors and Staff at Gulf Coast Veterinary Oncology! Don't forget to check our web site for the latest information at our Houston, Tomball and San Antonio locations! THIS WEEK'S TUMOR TIDBIT: RESISTANCE TO CHEMOTHERAPY Tumors may be intrinsically resistant to anticancer drugs or they may acquire resistance as a result of exposure. A tumor cell may be naturally unaffected by the mode of action of a chemotherapeutic agent; the cell may not have receptors or activating enzymes for the drug or may not be reliant on the biochemical process in which the drug interferes. In addition, some anatomical locations are difficult to treat with chemotherapy because of the inability of the drug to reach the site of the tumor (e.g., blood-brain barrier). Furthermore, drugs may not reach all cells in a poorly vascularized tumor, and these cells may survive in a quiescent state to reemerge at a later time. Acquired resistance develops after tumor cells have been exposed to a drug or similar class of drugs. Spontaneous mutation is assumed to be ongoing regardless of the presence of any drug and the occurrence of spontaneously resistant cells in a population approximates the rate of mutation. The rate of spontaneous genetic mutation in both normal and neoplastic cell populations is generally estimated at 10-7-10-5 per mitosis. If the population is then exposed to the drug, the resistant cell will have a growth advantage. Many chemotherapy agents are mutagenic and may increase the risk of development of clones that are resistant to one or more drugs. Thus, the larger the number of cells in a tumor, the more likely it is that spontaneous resistance will occur. If only a small subset, or clone, has the resistant phenotype, it will eventually become the dominant cell type in the tumor because of the growth advantage conferred by its ability to grow in the presence of a given drug. This may not be clinically evident if most of the tumor is sensitive until the resistant clone reaches a certain size. This is one of the mechanisms of relapse. Gene amplification is another source of acquired drug resistance that is enhanced by the presence of gradually increasing concentrations of the drug. Drugs such as mitotic inhibitors which promote a delay in the cell cycle just prior to M phase, are most likely to promote this phenomenon. A good example of acquired drug resistance by gene amplification is the multiple drug resistance phenotype. Multiple drug resistance (MDR) is a phenomenon of cross resistance of cells to a variety of agents which are not structurally or functionally related. These include the antitumor antibiotics, podophyllotoxins, and the plant alkaloids. MDR is mediated by p-glycoprotein, a cell membrane pump that is present normally on the surface of some epithelial cells. The protein actively removes drug from the cell, making it resistant to any drugs that are substrates for the pump. WHAT DO WE DO AT GULF COAST? For now, we are evaluating for the presence or absence of the MDR phenotype in lymphoma, osteosarcoma, and fibrosarcoma tumor types of dogs and cats at initial presentation and a various times during the pet's ongoing chemotherapy. It has helped us modify our protocols for each of these tumor types and select the best combination of therapies to fight the cancer. As more information becomes available, our hope is to find effective means for blocking this aspect of drug resistance. Don't hesitate to call or email us at Gulf Coast Veterinary Oncology! ALL THE BEST AND HAVE A GREAT HOLIDAY SEASON, Kevin A. Hahn, DVM, PhD Diplomate ACVIM (Oncology) & Overall Nice Guy Gulf Coast Veterinary Specialists 1111 West Loop South, Suite 150 Houston, TX 77027 P: 713.693.1166 F: 713.693.1167 http://www.gcvs.com mailto:drhahn@gulfcoastvetspec.com