PO-217 Loss of Kmt2c methyltransferase activity contributes to prostate tumorigenesis in a mouse model of prostate cancer

Abstract

IntroductionThe B6;129-Rag2tm1FwaIL2rgtm1Rsky/DwlHsd (R2G2) knockout mouse was developed by backcrossing an IL2rg (common gamma) knockout model to a RAG2 (recombinase activating gene) knockout model. The resulting mouse lacks various cytokines including IL-2, IL-4, IL-7, IL-9 and IL-15. In addition, this model lacks B cells, T cells, NK cells and has a deficit in lymphocyte development. This model was developed to provide another immunodeficient option for the oncology and immunology fields. The literature supports better tolerability of DNA damaging oncology treatments for models that do not carry the SCID mutation. We have already reported in a white paper that the R2G2 mouse model is more tolerant of whole body radiation than a model with the SCID mutation. Herein we describe a study examining chemotherapeutic tolerability of common DNA damaging oncology drugs including 5-fluorouracil (5-FU), doxorubicin (Doxo), and cyclophosphamide (CTX) (n=10 per group).Material and methods5-FU was given at 30, 60 or 100 mg/kg, intraperitoneally, twice weekly for five weeks. Doxo was given at 2 or 5 mg/kg, intraperitoneally, once weekly for three weeks. CTX was given at 100 or 140 mg/kg intraperitoneally, once weekly for three weeks. The low dose was chosen based on the average dose used in immunodeficient mouse models and the high dose was chosen based on the average dose used in immunocompetent mouse models. This was done to determine if the R2G2 mouse model can tolerate higher doses of these chemotherapeutic agents compared to other immunodeficient mouse models.Results and discussionsResults show that the R2G2 mouse model tolerates higher doses of these chemotherapeutic drugs than doses found in the literature for SCID models. Exogenous oestrogen tolerance is another common concern in oncology research as some immunodeficient mouse models cannot tolerate the subcutaneous oestrogen pellets, developing negative secondary effects resulting in removal from study. We performed an oestrogen pellet dose response study using four doses of 60 day release 17-β estradiol pellets at 0.18, 0.36, 0.72, and 1.7 mg/pellet (n=10 per group). R2G2 mice show dose dependent effects of oestrogen on morbidity. These data will allow researchers to determine the optimal dose for use in the R2G2 model.ConclusionIn conclusion, these data support that the R2G2 mouse model may be a good alternative to SCID models when administering DNA damaging chemotherapies or when oestrogen supplementation is required for xenograft growth.