Comparison of three rapamycin dosing schedules in A-J Tsc2 - mice and improved survival with angiogenesis inhibitor or asparaginase treatment in mice with subcutaneous tuberous sclerosis related tumorsReportar como inadecuado




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Journal of Translational Medicine

, 8:14

First Online: 10 February 2010Received: 30 September 2009Accepted: 10 February 2010DOI: 10.1186-1479-5876-8-14

Cite this article as: Woodrum, C., Nobil, A. & Dabora, S.L. J Transl Med 2010 8: 14. doi:10.1186-1479-5876-8-14

Abstract

BackgroundTuberous Sclerosis Complex TSC is an autosomal dominant tumor disorder characterized by the growth of hamartomas in various organs including the kidney, brain, skin, lungs, and heart. Rapamycin has been shown to reduce the size of kidney angiomyolipomas associated with TSC; however, tumor regression is incomplete and kidney angiomyolipomas regrow after cessation of treatment. Mouse models of TSC2 related tumors are useful for evaluating new approaches to drug therapy for TSC.

MethodsIn cohorts of Tsc2 mice, we compared kidney cystadenoma severity in A-J and C57BL-6 mouse strains at both 9 and 12 months of age. We also investigated age related kidney tumor progression and compared three different rapamycin treatment schedules in cohorts of A-J Tsc2 mice. In addition, we used nude mice bearing Tsc2 subcutaneous tumors to evaluate the therapeutic utility of sunitinib, bevacizumab, vincristine, and asparaginase.

ResultsTSC related kidney disease severity is 5-10 fold higher in A-J Tsc2 mice compared with C57BL-6 Tsc2 mice. Similar to kidney angiomyolipomas associated with TSC, the severity of kidney cystadenomas increases with age in A-J Tsc2 mice. When rapamycin dosing schedules were compared in A-J Tsc2 cohorts, we observed a 66% reduction in kidney tumor burden in mice treated daily for 4 weeks, an 82% reduction in mice treated daily for 4 weeks followed by weekly for 8 weeks, and an 81% reduction in mice treated weekly for 12 weeks. In the Tsc2 subcutaneous tumor mouse model, vincristine is not effective, but angiogenesis inhibitors sunitinib and bevacizumab and asparaginase are effective as single agents. However, these drugs are not as effective as rapamycin in that they increased median survival only by 24-27%, while rapamycin increased median survival by 173%.

ConclusionsOur results indicate that the A-J Tsc2 mouse model is an improved, higher through-put mouse model for future TSC preclinical studies. The rapamycin dosing comparison study indicates that the duration of rapamycin treatment is more important than dose intensity. We also found that angiogenesis inhibitors and asparaginase reduce tumor growth in a TSC2 tumor mouse model and although these drugs are not as effective as rapamycin, these drug classes may have some therapeutic potential in the treatment of TSC related tumors.

Electronic supplementary materialThe online version of this article doi:10.1186-1479-5876-8-14 contains supplementary material, which is available to authorized users.

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Autor: Chelsey Woodrum - Alison Nobil - Sandra L Dabora

Fuente: https://link.springer.com/



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