Farmakogenomikens betydelse för individvariationen avseende biverkningar och resultat vid Paclitaxel behandling av hund

Abstract: Purpose The purpose of this study is to evaluate the treatment results and adverse drug effects for 14 dogs receiving a new paclitaxel preparat named Paccal vet. The evaluated dogs are chosen to enter a pharmacogenomical study. Therefore, this paper intends to give an introduction to pharmacogenomics. Finally this study also aims at finding the homologue genesequenses in dogs to seven genes that are important for metabolism of paclitaxel in humans. Materials and metods The dogs went through 2-4 cycles of paclitaxel treatment, they received a new water-soluble formula named Paccal vet, at dosages of 100-150mg/m2. Treatment results and adverse effects are listed for each dog in table 1. Gastrointestinal side effects are listed once per dog, bone marrow suppression is listed for each cycle. The dogs’ DNA is prepared from frozen EDTA-bloodsamples. As a result of the creation of different breeds, dogs have very long haplotypes, in which no recombination occurs. Therefore there can’t be an easily accessed map of haplotypes. Instead, one have to assume that by using at least five SNPs per gene of interest all different haplotypes can be covered. After deciding which SNPs to use, the primers for amplifying can be designed by help of different computer programmes. Results All dogs tolerated the substance well; no sensitivity reactions were observed. The most frequent side-effects were bone marrow depression and gastrointestinal upset. At an initial search for the homologue sequences of the chosen genes, only a few were found. The same sequence also showed up for different genes, thus revealing that it may be quite complicated to find the desired homologues, much due to the fact that some of the genes are very similar to each other. Conclusions The fact that dogs seem to tolerate Paccal vet, and the side-effects being manageable, gives a promising future to further studies following up on this small pilot study. It is the first cytostatica made particularly for dogs and also the first paclitaxel preparat tolerated by dogs. However it is a study of very few dogs whom varied greatly in gender, breed, age and size. They also suffered from different diseases in different stages which makes the results unreliable. The further farmacogenomic study of these dogs can although it is small be of great importance. It can show whether the canine genome shows polymorphism in those genes or not. If so, analysis of the results may strengthen the hypothesis that this polymorphism is strongly responsible for the individual variations in dogs as well. The concept of individualizing cancer therapy is one of great appeal, and world wide scientists are digging in to farmacogenomics. Only the future can answer how it will be applied in veterinary medicine. First we need to establish that polymorphism of interesting genes span over breed boundaries, thus it is unrealistic to keep one gene map per breed. However, if this is the case, farmacogenomic testing can prove to be of great value. For dogs with cancer, euthanasia often is a considered alternative, which puts the pet owner and sometimes also the veterinarian in a tough position. It would be of immeasurable value if a simple test could be taken, that answers the question whether this patient has a low or high probability to benefit from treatment.