Thymosin alpha 1 - From bench to bedside
Thymosin alpha 1 - From bench to bedside
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DOI：
10.1196/annals.1415.044
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发表时间：
2007-01-01
期刊：
影响因子：
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通讯作者：
Rasi, Guido
中科院分区：
文献类型：
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作者：
Garaci, Enrico;Favalli, Cartesio;Rasi, Guido
在Lewis肺癌动物模型中观察到最初的显著效果后，在环磷酰胺后使用胸腺素α1(Tα1)和干扰素(干扰素)，在小鼠(Friend红白血病和B16黑色素瘤)和大鼠(DHD/K12结直肠癌肝转移)的其他一些临床前模型中，已经证实了Tα1和干扰素或IL-2加化疗的联合治疗效果。这些结果为Tα1联合BRM和/或化疗的首次临床试验提供了科学依据。对晚期非小细胞肺癌(NSCLC)和黑色素瘤的关键试验表明，在顺铂或达卡巴肼治疗后，Tα1和干扰素-α的低剂量治疗首次证明了这种方法在治疗人类癌症方面的高潜力。Tα1和干扰素-α的联合应用也被用于慢性乙型和丙型肝炎患者，包括干扰素无应答者和感染前C区突变或1b基因型的患者。进一步的研究证实了Tα1的额外生物学活性，阐明了Tα1的作用机制，部分解释了Tα1与干扰素的协同作用。已有研究表明，它能够通过Toll样受体信号激活感染的树突状细胞，从而影响炎症平衡，并增加肿瘤、病毒和主要组织相容性复合体(MHC)I抗原的表达。剂量反应研究表明，这种分子有可能提高疗效，降低总体毒性。基于这些信息，两项临床试验正在进行中：一项是关于在达卡巴肼之后接受不同剂量Tα1治疗的晚期黑色素瘤患者的大型II期试验，另一项是关于采用三联疗法(干扰素、利巴韦林和Tα1)治疗的抗干扰素丙型肝炎病毒(HCV)患者的III期试验。
After the initial dramatic effects, observed in a Lewis lung carcinoma animal model, using a combination of thymosin alpha 1 (T alpha 1) and interferon (IFN) after cyclophosphamide, a number of other preclinical models in mice (Friend erythroleukemia and B16 melanoma) and in rats (DHD/K12 colorectal cancer liver metastasis) have confirmed the efficacy of the combination therapy with T alpha 1 and either IFN or IL-2 plus chemotherapy. These results provided the scientific foundation for the first clinical trials using T alpha 1 in combination with BRMs and/or chemotherapy. Pivotal trials in advanced non-small cell lung cancer (NSCLC) and melanoma with T alpha 1 and IFN-alpha low doses after cis-platinum or dacarbazine produced the first evidence of the high potentiality of this approach in the treatment of human cancer. The combination of T alpha 1 and IFN-alpha was also used in patients affected by chronic B and C hepatitis including IFN-nonresponders and infected by precore mutants or genotype 1b. Further studies demonstrated additional biological activities clarifying the mechanism of action of T alpha 1, partially explaining the synergism with IFN. It has been shown the capacity of activating infected dendritic cells through Toll-like receptor signaling, thus influencing the inflammation balance, and of increasing the expression of tumor, viral, and major histocompatibility complex (MHC) I antigens. Dose-response studies suggested the possibility of improving the efficacy of this molecule reducing the overall toxic. Based on these information two clinical trials are ongoing: a large phase II on advanced melanoma patients treated with T alpha 1 at different doses after dacarbazine and a phase III one, on IFN-resistant hepatitis C virus (HCV) patients treated with a triple combination (IFN, ribavirin, and T alpha 1).