Interestingly, the A J Tsc2 strain shows a substantially greater tumor burden at five months of age than the C57BL 6 Tsc2 strain at 12 months of age. Depending on the findings of this study, the A J strain Tsc2 mice possess a 5 10 fold larger disease burden than C57BL 6 strain Tsc2 mice and are a superior and larger through put Tsc2 mouse model for preclinical research relevant to TSC kidney disease and tumors. In addition, since there is a dramatic distinction within the severity with the kidney tumor phenotype in these two mouse strains, they could possibly be made use of to recognize modifier genes that impact the severity of TSC renal manifestations. The prospective utility of rapamycin treatment for a pro longed duration was recommended by the results of a pre vious preclinical study employing C57BL six Tsc2 mice in which we noted that a rapamycin dosing schedule that included each day treatment for two months and weekly treat ment for six months, resulted in a dramatic 94.
5% reduc tion in kidney tumor severity. In that study, rapamycin was given at a dose of eight mg kg Monday through Friday from 6 to 7 months of age, followed by a maintenance dose of 16 mg kg once per week from 7 to 12 months of age, followed by each day rapamycin treat ment from 12 to 13 months of age. We also note that in PF-04691502 solubility preceding CCI 779 preclinical research, giving a reduce dose more than three months seemed to be far more powerful than a larger dose for two months. We found that opti mal remedy correlated with duration of treatment, not total dose offered. There was a 66% reduction having a total dose of 4. eight mg per mouse inside the group treated every day ? four weeks, an 82% reduction using a total dose of 6.
72 mg per mouse in the group treated day-to-day ? 4 weeks plus weekly ? eight weeks, and an 81% reduction having a total dose of 2. 88 mg per mouse in the group treated weekly ? 12 weeks. These findings demon strate that low dose rapamycin PCI-34051 molecular weight mw therapy for any longer duration of time is most successful inside the Tsc2 mouse, and it could be affordable to evaluate this dosing strat egy in future TSC clinical trials. Our findings also clearly demonstrate that the response of kidney tumors to rapamycin in the Tsc2 mouse correlates properly with observations in early TSC angiomyolipoma clinical trials. Within a J Tsc2 mice, cystadenoma score per kidney in untreated animals at 9 months of age is 74. four, and cystadenoma score per kid ney is 41. 13 in the groups treated each day ? 4 weeks, but 21. 50 in the group treated every day ? 4 weeks then weekly ? 8 weeks. Moreover, the larger kidney tumor score in the group treated every day ? 4 weeks is consistent with tumor regrowth through months ten 12 when no drug therapy was offered. This result is analogous to what is observed in individuals with kidney angiomyolipomas connected with TSC and or LAM treated with rapamycin.