Su Z, Lebedeva I V, Gopalkrishnan R V, Goldstein N I, Stein C A, Reed J C, Dent P, Fisher P B
Department of Urology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10332-7. doi: 10.1073/pnas.171315198.
Pancreatic cancer is an extremely aggressive neoplasm whose incidence equals its death rate. Despite intensive analysis, the genetic changes that mediate pancreatic cancer development and effective therapies for diminishing the morbidity associated with this disease remain unresolved. Through subtraction hybridization, we have identified a gene associated with induction of irreversible growth arrest, cancer reversion, and terminal differentiation in human melanoma cells, melanoma differentiation associated gene-7 (mda-7). Ectopic expression of mda-7 when using a recombinant adenovirus, Ad.mda-7, results in growth suppression and apoptosis in a broad spectrum of human cancers with diverse genetic defects, without exerting deleterious effects in normal human epithelial or fibroblast cells. Despite the apparently ubiquitous antitumor effects of mda-7, pancreatic carcinoma cells are remarkably refractory to Ad.mda-7 induced growth suppression and apoptosis. In contrast, the combination of Ad.mda-7 with antisense phosphorothioate oligonucleotides, which target the K-ras oncogene (a gene that is mutated in 85 to 95% of pancreatic carcinomas), induces a dramatic suppression in growth and a decrease in cell viability by induction of apoptosis. In mutant K-ras pancreatic carcinoma cells, programmed cell death correlates with expression and an increase, respectively, in MDA-7 and BAX proteins and increases in the ratio of BAX to BCL-2 proteins. Moreover, transfection of mutant K-ras pancreatic carcinoma cells with an antisense K-ras expression vector and infection with Ad.mda-7 inhibits colony formation in vitro and tumorigenesis in vivo in nude mice. These intriguing observations demonstrate that a combinatorial approach, consisting of a cancer-specific apoptosis-inducing gene and an oncogene inactivation strategy, may provide the foundation for developing an effective therapy for pancreatic cancer.
胰腺癌是一种极具侵袭性的肿瘤，其发病率与死亡率相当。尽管进行了深入分析，但介导胰腺癌发展的基因变化以及降低该疾病相关发病率的有效疗法仍未得到解决。通过消减杂交，我们在人类黑色素瘤细胞中鉴定出一种与诱导不可逆生长停滞、癌症逆转和终末分化相关的基因，即黑色素瘤分化相关基因-7（mda-7）。使用重组腺病毒Ad.mda-7异位表达mda-7，可导致多种具有不同遗传缺陷的人类癌症发生生长抑制和凋亡，而对正常人类上皮细胞或成纤维细胞无有害影响。尽管mda-7具有明显普遍的抗肿瘤作用，但胰腺癌细胞对Ad.mda-7诱导的生长抑制和凋亡具有显著抗性。相比之下Ad.mda-7与针对K-ras癌基因（在85%至95%的胰腺癌中发生突变的基因）的反义硫代磷酸酯寡核苷酸联合使用，可通过诱导凋亡显著抑制生长并降低细胞活力。在突变型K-ras胰腺癌细胞中，程序性细胞死亡分别与MDA-7和BAX蛋白的表达增加以及BAX与BCL-2蛋白比例的增加相关。此外，用反义K-ras表达载体转染突变型K-ras胰腺癌细胞并感染Ad.mda-7可抑制体外集落形成和裸鼠体内肿瘤发生。这些有趣的观察结果表明，由癌症特异性凋亡诱导基因和癌基因失活策略组成的联合方法可能为开发有效的胰腺癌治疗方法提供基础。
