Rovithi Maria, de Haas Richard R, Honeywell Richard J, Poel Dennis, Peters Godefridus J, Griffioen Arjan W, Verheul Henk M W
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
J Exp Clin Cancer Res. 2016 Sep 7;35(1):138. doi: 10.1186/s13046-016-0411-2.
Increased exposure to multitargeted kinase inhibitor sunitinib is associated with improved outcome, emphasizing the importance of maintaining adequate dosing and drug levels. The currently approved schedule (50 mg daily, four weeks on, two weeks off) precludes further dose-intensification. Recent data suggest that sunitinib, although initially developed as an antiangiogenic agent, has direct antitumor activity.
In this study, we tested whether a chemotherapy-like schedule of pulsatile high dose sunitinib would result in improved antitumor activity.
In vitro, a single exposure to 20 μM sunitinib for 6-9 h resulted in complete inhibition of tumor cell growth and cell death conveyed through activation of caspases and autophagy upregulation. Notably, repeated exposure of tumor cells to pulses of high concentrations of sunitinib did not induce resistance. In vivo, once-weekly treatment with high dose sunitinib of tumors growing on the chorioallantoic membrane (CAM) of the chicken embryo significantly impaired tumor growth by 57 % compared to vehicle, outperforming the daily, standard scheduling.
These results prompted the initiation of a phase I clinical trial, where intermittent, high dose sunitinib is being investigated in patients with advanced solid tumors (registration number and date: NCT02058901, 30 September 2013, respectively). The trial is actively recruiting patients and promising preliminary indications of antitumor activity have been observed.
多靶点激酶抑制剂舒尼替尼暴露量增加与预后改善相关，这凸显了维持足够剂量和药物水平的重要性。目前批准的给药方案（每日50毫克，服用四周，停药两周）排除了进一步增加剂量的可能性。近期数据表明，舒尼替尼虽然最初是作为一种抗血管生成药物开发的，但具有直接抗肿瘤活性。
在本研究中，我们测试了类似化疗方案的脉冲式高剂量舒尼替尼是否会带来更好的抗肿瘤活性。
在体外，单次暴露于20μM舒尼替尼6至9小时可导致肿瘤细胞生长完全抑制，并通过半胱天冬酶激活和自噬上调导致细胞死亡。值得注意的是，肿瘤细胞反复暴露于高浓度舒尼替尼脉冲中并未诱导耐药性。在体内，与赋形剂相比，每周一次用高剂量舒尼替尼治疗鸡胚尿囊膜（CAM）上生长的肿瘤，可使肿瘤生长显著受损57%，优于每日标准给药方案。
这些结果促使开展了一项I期临床试验，在晚期实体瘤患者中研究间歇性高剂量舒尼替尼（注册号和日期：分别为NCT02058901、2013年9月30日）。该试验正在积极招募患者，并且已经观察到有前景的抗肿瘤活性初步迹象。
