Development of novel therapeutic strategies based on the molecular analyses of tumor cells in animal lymphomas

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For the past 30 years, a large number of therapeutic clinical trials for canine lymphoid tumors were reported; however, apparent improvement on the outcome of the patients has not been obtained. The present study was carried out to aim at the development of novel therapeutic strategies based upon the molecular analyses of the tumor cells.With respect to the drug resistance of the tumor cells, drug efflux pumps, drug metabolizing molecules, cell cycle-regulating molecules, and apoptosis-associated molecules were examined. The results indicated that increased expression of P-glycoprotein (P-gp), one of the drug efflux pump, and mutation of p53 gene encoding cell cycle/apoptosis-associated molecule were found in drug-resistant lymphoid tumors in dogs.Next, we established an assay system to quantify the copy number of rearranged immunoglobulin and T-cell receptor genes in lymphoid cells. The assay system enabled the quantification of a small number of residual tumor cells after chemotherapy, namely minimal residual disease (MRD). MRD could be detected in dogs even after induction of complete remission and gradually increased 1～2 months before relapse. The amount of MRD at the end of chemotherapy was negatively correlated with the remission duration until relapse. These findings indicated that the MRD could be an objective marker to compare the efficacy of different chemotherapeutic protocols and a negative prognostic factor for the relapse in canine lymphoma. Furthermore, the present study introduced a tailor-made therapy based on the MRD level in each phase/patient.Because the lymphoid tumors in dogs can be recognized as an animal model of the human disease, the present study provided useful information to develop novel therapeutic strategies in lymphoid tumors in humans.