Yale University School of Medicine, New Haven, CT 06520, USA.
Sci Transl Med. 2010 Aug 18;2(45):45ra59. doi: 10.1126/scitranslmed.3001270.
PHY906, a four-herb Chinese medicine formula first described 1800 years ago, decreases gastrointestinal toxicity induced by the chemotherapeutic drug CPT-11 (irinotecan), as shown in a phase I/II clinical study. Similarly, in a murine colon 38 allograft model, PHY906 increased the antitumor activity of CPT-11 while decreasing animal weight loss caused by CPT-11. Here, we have further examined the effect of PHY906 on the intestinal toxicity caused by CPT-11 in mice. PHY906 did not protect against the initial DNA damage and apoptosis triggered by CPT-11 in the intestine, but by 4 days after CPT-11 treatment, PHY906 had restored the intestinal epithelium by promoting the regeneration of intestinal progenitor or stem cells and several Wnt signaling components. PHY906 also potentiated Wnt3a activity in human embryonic kidney-293 cells. Furthermore, PHY906 exhibited anti-inflammatory effects in mice by decreasing the infiltration of neutrophils or macrophages, tumor necrosis factor-alpha expression in the intestine, and proinflammatory cytokine concentrations in plasma. Chemical constituents of PHY906 potently inhibited nuclear factor kappaB, cyclooxygenase-2, and inducible nitric oxide synthase. Our results show that the herbal medicine PHY906 can counteract the toxicity of CPT-11 via several mechanisms that act simultaneously.
PHY906 是一种四味中药配方，最早在 1800 年前被描述，可降低化疗药物伊立替康（CPT-11）引起的胃肠道毒性，这在一项 I/II 期临床试验中得到了证实。同样，在小鼠结肠 38 同种异体移植模型中，PHY906 增加了 CPT-11 的抗肿瘤活性，同时减少了 CPT-11 引起的动物体重减轻。在这里，我们进一步研究了 PHY906 对 CPT-11 引起的小鼠肠道毒性的影响。PHY906 不能预防 CPT-11 在肠道中引发的初始 DNA 损伤和细胞凋亡，但在 CPT-11 治疗 4 天后，PHY906 通过促进肠前体细胞或干细胞的再生和几种 Wnt 信号成分，恢复了肠道上皮。PHY906 还增强了人胚肾-293 细胞中 Wnt3a 的活性。此外，PHY906 通过减少中性粒细胞或巨噬细胞的浸润、肠道中肿瘤坏死因子-α的表达和血浆中促炎细胞因子的浓度，在小鼠中表现出抗炎作用。PHY906 的化学成分强烈抑制核因子 kappaB、环氧化酶-2 和诱导型一氧化氮合酶。我们的结果表明，草药 PHY906 可以通过几种同时作用的机制来对抗 CPT-11 的毒性。
