Molecular target-based therapy of pancreatic cancer
Molecular target-based therapy of pancreatic cancer
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DOI：
10.1158/0008-5472.can-05-3510
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发表时间：
2006-02-15
期刊：
影响因子：
11.2
通讯作者：
Fisher, PB
中科院分区：
文献类型：
--
作者：
Lebedeva, IV;Sarkar, D;Fisher, PB
胰腺癌是一种复杂的遗传疾病，目前尚无有效的治疗方法。Kirsten-ras（K-ras）癌基因突变在胰腺癌发生和进展过程中早期和频繁发生（接近90%）。在这种情况下，K-ras代表了治疗这种高度侵袭性癌症的潜在分子靶点。我们现在表明，一个二分腺病毒表达一种新的癌症特异性肿瘤诱导细胞因子基因，mda-7/白细胞介素-24（IL-24），和K-ras AS基因，但不是单独的基因，促进生长抑制，诱导细胞凋亡，并抑制K-ras突变胰腺癌细胞介导的肿瘤发展。同样，表达mda-7/IL-24的腺病毒与同时阻断K-ras或下游细胞外调节激酶1/2信号传导的药理学和遗传学试剂的组合也促进对K-ras突变胰腺癌细胞的生长和存活的类似抑制作用。这种活性与胰腺癌细胞中mda-7/IL-24 mRNA翻译阻断的逆转相关，该逆转限制了与多核糖体的信息结合，从而阻碍了翻译成蛋白质。我们的研究为“双分子靶向治疗”提供了支持，该治疗涉及癌基因抑制和选择性癌症转移诱导基因表达，具有有效治疗总是致命的癌症的潜力。
Pancreatic cancer is genetically complex, and without effective therapy. Mutations in the Kirsten-ras (K-ras) oncogene occur early and frequently (similar to 90%) during pancreatic cancer development and progression. In this context, K-ras represents a potential molecular target for the therapy of this highly aggressive cancer. We now show that a bipartite adenovirus expressing a novel cancer-specific apoptosis-inducing cytokine gene, mda-7/interleukin-24 (IL-24), and a K-ras AS gene, but not either gene alone, promotes growth suppression, induction of apoptosis, and suppression of tumor development mediated by K-ras mutant pancreatic cancer cells. Equally, the combination of an adenovirus expressing mda-7/IL-24 and pharmacologic and genetic agents simultaneously blocking K-ras or downstream extracellular regulated kinase 1/2 signaling also promotes similar inhibitory effects on the growth and survival of K-ras mutant pancreatic carcinoma cells. This activity correlates with the reversal of a translational block in mda-7/IL-24 mRNA in pancreatic cancer cells that limits message association with polysomes, thereby impeding translation into protein. Our study provides support for a "dual molecular targeted therapy" involving oncogene inhibition and selective cancer apoptosis-inducing gene expression with potential for effectively treating an invariably fatal cancer.