Gupta Pankaj, Su Zao-zhong, Lebedeva Irina V, Sarkar Devanand, Sauane Moira, Emdad Luni, Bachelor Michael A, Grant Steven, Curiel David T, Dent Paul, Fisher Paul B
Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, United States.
Pharmacol Ther. 2006 Sep;111(3):596-628. doi: 10.1016/j.pharmthera.2005.11.005. Epub 2006 Feb 7.
"Differentiation therapy" provides a unique and potentially effective, less toxic treatment paradigm for cancer. Moreover, combining "differentiation therapy" with molecular approaches presents an unparalleled opportunity to identify and clone genes mediating cancer growth control, differentiation, senescence, and programmed cell death (apoptosis). Subtraction hybridization applied to human melanoma cells induced to terminally differentiate by treatment with fibroblast interferon (IFN-beta) plus mezerein (MEZ) permitted cloning of melanoma differentiation associated (mda) genes. Founded on its novel properties, one particular mda gene, mda-7, now classified as a member of the interleukin (IL)-10 gene family (IL-24) because of conserved structure, chromosomal location, and cytokine-like properties has become the focus of attention of multiple laboratories. When administered by transfection or adenovirus-transduction into a spectrum of tumor cell types, melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) induces apoptosis, whereas no toxicity is apparent in normal cells. mda-7/IL-24 displays potent "bystander antitumor" activity and also has the capacity to enhance radiation lethality, to induce immune-regulatory activities, and to inhibit tumor angiogenesis. Based on these remarkable attributes and effective antitumor therapy in animal models, this cytokine has taken the important step of entering the clinic. In a Phase I clinical trial, intratumoral injections of adenovirus-administered mda-7/IL-24 (Ad.mda-7) was safe, elicited tumor-regulatory and immune-activating processes, and provided clinically significant activity. This review highlights our current understanding of the diverse activities and properties of this novel cytokine, with potential to become a prominent gene therapy for cancer.
“分化疗法”为癌症提供了一种独特且可能有效的低毒治疗模式。此外，将“分化疗法”与分子方法相结合，为识别和克隆介导癌症生长控制、分化、衰老及程序性细胞死亡（凋亡）的基因提供了无与伦比的机会。应用消减杂交技术，对经成纤维细胞干扰素（IFN-β）加狼毒素（MEZ）处理诱导终末分化的人黑色素瘤细胞进行研究，从而克隆出黑色素瘤分化相关（mda）基因。基于其独特性质，一个特定的mda基因，即mda-7，由于其保守的结构、染色体定位及细胞因子样特性，现被归类为白细胞介素（IL）-10基因家族（IL-24）的成员，已成为多个实验室关注的焦点。当通过转染或腺病毒转导将其导入多种肿瘤细胞类型时，黑色素瘤分化相关基因-7/白细胞介素-24（mda-7/IL-24）可诱导凋亡，而在正常细胞中未观察到明显毒性。mda-7/IL-24具有强大的“旁观者抗肿瘤”活性，还能够增强辐射杀伤力、诱导免疫调节活性并抑制肿瘤血管生成。基于这些显著特性以及在动物模型中的有效抗肿瘤治疗效果，这种细胞因子已迈出重要一步进入临床。在一项I期临床试验中，瘤内注射腺病毒介导的mda-7/IL-24（Ad.mda-7）是安全的，引发了肿瘤调节和免疫激活过程，并具有临床显著活性。本综述重点介绍了我们目前对这种新型细胞因子多样活性和特性的理解，其有望成为一种重要的癌症基因疗法。
