Mouse by Rofecoxib , a Specific Cyclooxygenase-2 Inhibitor 716 ∆ Apc Chemoprevention of Intestinal Polyposis in the Updated Version
Mouse by Rofecoxib , a Specific Cyclooxygenase-2 Inhibitor 716 ∆ Apc Chemoprevention of Intestinal Polyposis in the Updated Version
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发表时间：
2001
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通讯作者：
M. Oshima;Naomi Murai Hata;S. Kargman;Meztli Arguello;P. Luk;E. Kwong;M. Taketo;Jilly F. Evans
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作者：
M. Oshima;Naomi Murai Hata;S. Kargman;Meztli Arguello;P. Luk;E. Kwong;M. Taketo;Jilly F. Evans
人类腺瘤性息肉病 (APC) 基因突变是家族性腺瘤性息肉病 (FAP) 的病因，这是一种罕见疾病，青春期期间会出现大量结肠息肉，如果不及时治疗，会导致结肠癌。 APC基因是一种肿瘤抑制基因，被称为结肠癌的“看门基因”。除了FAP患者中100%的突变率之外，APC基因在>80%的散发性结肠癌和肠癌中也发生突变。小鼠中的 Apc 基因已通过化学致癌作用发生突变，产生 Min 小鼠 Apc，或者通过异源重组发生突变，产生 theApc 或 Apc 小鼠（M. Oshima 等，Proc. Natl. Acad. Sci. USA，92：4482-4486，1995）。虽然纯合Apc小鼠在胚胎上是致命的，但杂合子是可存活的，但会形成大量肠息肉，且息肉内Apc杂合性丧失（M. Oshimaet al., Proc. Natl. Acad. Sci. USA, 92: 4482–4486, 1995）。促炎、促癌蛋白环氧合酶 (COX)-2 已被证明在息肉发育的早期阶段在 Apc 息肉中被显着诱导 (M. Oshimaet al., Cell,87: 803–809, 1996)。我们在此证明，用特定的COX-2抑制剂罗非昔布治疗可导致Apc小鼠中肠和结肠息肉的数量和大小呈剂量依赖性减少。导致息肉数量抑制 55% 和尺寸 >1mm 息肉抑制 80% 的罗非考昔血浆浓度与每日一次服用 25 mg 罗非考昔 (Vioxx) 的人类临床稳态浓度相当 (A. Porraset al., Clin. Pharm. Ther., 67: 137, 2000)。未经治疗和罗非考昔硼舒林酸治疗的 Apc 小鼠的息肉均表达 COX-1 和 -2，而所有小鼠的正常上皮均表达 COX-1，但表达极少量的 COX-2。罗非考昔硼舒林酸治疗小鼠的息肉具有较低的 DNA 复制率，表达较少的促血管生成血管内皮衍生生长因子和较多的膜结合 β-连环蛋白，但该转录因子的核定位未发生变化。这项研究显示了 Apc 小鼠息肉病的抑制作用，表明特异性 COX-2 抑制剂罗非考昔 (Vioxx) 具有作为人类肠癌和结肠癌化学预防剂的潜力。
Mutations in the human adenomatous polyposis (APC) gene are causative for familial adenomatous polyposis (FAP), a rare condition in which numerous colonic polyps arise during puberty and, if left untreated, lead to colon cancer. TheAPCgene is a tumor suppressor that has been termed the “gatekeeper gene” for colon cancer. In addition to the 100% mutation rate in FAP patients, theAPC gene is mutated in>80% of sporadic colon and intestinal cancers. TheApc gene in mice has been mutated either by chemical carcinogenesis, resulting in the Min mouseApc, or by heterologous recombination, resulting in theApc or Apc mice (M. Oshima et al., Proc. Natl. Acad. Sci. USA, 92: 4482–4486, 1995). Although homozygoteApc mice are embryonically lethal, the heterozygotes are viable but develop numerous intestinal polyps with loss of Apc heterozygosity within the polyps (M. Oshimaet al., Proc. Natl. Acad. Sci. USA,92: 4482–4486, 1995). The proinflammatory, prooncogenic protein cyclooxygenase (COX)-2 has been shown to be markedly induced in the Apc polyps at an early stage of polyp development (M. Oshimaet al., Cell,87: 803–809, 1996). We demonstrate here that treatment with the specific COX-2 inhibitor rofecoxib results in a dose-dependent reduction in the number and size of intestinal and colonic polyps in theApcmouse. The plasma concentration of rofecoxib that resulted in a 55% inhibition of polyp number and an 80% inhibition of polyps >1 mm in size is comparable with the human clinical steady-state concentration of 25 mg rofecoxib (Vioxx) taken once daily (A. Porraset al., Clin. Pharm. Ther., 67: 137, 2000). Polyps from both untreated and rofecoxibor sulindac-treated Apc mice expressed COX-1 and -2, whereas normal epithelium from all mice expressed COX-1 but minimal amounts of COX-2. Polyps from either rofecoxibor sulindac-treated mice had lower rates of DNA replication, expressed less proangiogenic vascular endothelial-derived growth factor and more membrane-bound b-catenin, but showed unchanged nuclear localization of this transcription factor. This study showing the inhibition of polyposis in the Apc mouse suggests that the specific COX-2 inhibitor rofecoxib (Vioxx) has potential as a chemopreventive agent in human intestinal and colon cancer.