Translational Medicine Division, Department of Medicine, Brigham & Women's Hospital, Karp Building, Boston, MA, USA.
J Transl Med. 2010 Feb 10;8:14. doi: 10.1186/1479-5876-8-14.
Tuberous 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.
In 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.
TSC 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%.
Our 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.
结节性硬化症（TSC）是一种常染色体显性遗传的肿瘤疾病，其特征是在肾脏、大脑、皮肤、肺部和心脏等各种器官中生长错构瘤。雷帕霉素已被证明可减少与 TSC 相关的肾血管平滑肌脂肪瘤的大小；然而，肿瘤消退不完全，并且在停止治疗后肾血管平滑肌脂肪瘤会重新生长。TSC2 相关肿瘤的小鼠模型可用于评估 TSC 药物治疗的新方法。
在 Tsc2+/- 小鼠的队列中，我们比较了 9 个月和 12 个月龄时 A/J 和 C57BL/6 小鼠品系的肾囊腺瘤严重程度。我们还研究了年龄相关的肾肿瘤进展，并在 A/J Tsc2+/- 小鼠的队列中比较了三种不同的雷帕霉素治疗方案。此外，我们使用携带 Tsc2-/- 皮下肿瘤的裸鼠来评估舒尼替尼、贝伐珠单抗、长春新碱和门冬酰胺酶的治疗效果。
与 C57BL/6 Tsc2+/- 小鼠相比，A/J Tsc2+/- 小鼠的 TSC 相关肾脏疾病严重程度高 5-10 倍。与 TSC 相关的肾血管平滑肌脂肪瘤相似，A/J Tsc2+/- 小鼠的肾囊腺瘤严重程度随年龄增长而增加。当比较 A/J Tsc2+/- 队列中的雷帕霉素剂量方案时，我们观察到每天治疗 4 周的小鼠肾脏肿瘤负担减少 66%，每天治疗 4 周后每周治疗 8 周的小鼠减少 82%，每周治疗 12 周的小鼠减少 81%。在 Tsc2-/- 皮下肿瘤小鼠模型中，长春新碱无效，但血管生成抑制剂（舒尼替尼和贝伐珠单抗）和门冬酰胺酶作为单一药物有效。然而，这些药物不如雷帕霉素有效，因为它们仅将中位生存期延长 24-27%，而雷帕霉素将中位生存期延长 173%。
我们的结果表明，A/J Tsc2+/- 小鼠模型是未来 TSC 临床前研究的一种改进的、更高通量的小鼠模型。雷帕霉素剂量比较研究表明，雷帕霉素治疗的持续时间比剂量强度更重要。我们还发现，血管生成抑制剂和门冬酰胺酶可减少 TSC2 肿瘤小鼠模型中的肿瘤生长，尽管这些药物不如雷帕霉素有效，但这些药物类别在治疗 TSC 相关肿瘤方面可能具有一定的治疗潜力。
