Hursting S D, Perkins S N, Phang J M
Laboratory of Nutritional and Molecular Regulation, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702.
Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7036-40. doi: 10.1073/pnas.91.15.7036.
Transgenic mice with both alleles of the p53 tumor suppressor gene (frequently mutated in human tumors) knocked out by gene targeting provide a potentially useful tumorigenesis model because these mice rapidly develop spontaneous tumors. To determine whether tumorigenesis in p53-knockout mice is sensitive to experimental manipulation, tumor development in response to calorie restriction (CR; a potent inhibitor of rodent tumors) was evaluated. Tumor development was monitored for 48 weeks in male nullizygous p53-knockout and wild-type littermate mice (28-30 per treatment group) fed ad libitum (AL) or restricted to 60% of AL carbohydrate calorie intake. CR:p53-knockout mice (median survival = 25 weeks) experienced a delay in tumor onset and subsequent mortality (P = 0.0002) relative to AL:p53-knockout mice (median survival = 16 weeks). Tumor development and mortality in wild-type littermates on either diet treatment were < 4% through 48 weeks. Cell cycle analyses were performed on splenocytes from p53-knockout mice and wild-type littermates after 4 weeks of AL feeding or CR (5 per group). The percentage of splenocytes in S phase of the cell cycle was 3-fold higher for p53-knockout mice than wild-type mice (P < 0.001), and CR reduced the percentage of S-phase splenocytes in both p53-knockout and wild-type mice (P = 0.012). These data demonstrate that tumor development in p53-knockout mice genetically predisposed to tumors can be delayed by CR (possibly via cell cycle modulation) and suggest that these mice provide a very useful model of spontaneous tumorigenesis.
通过基因打靶使肿瘤抑制基因p53的两个等位基因（在人类肿瘤中经常发生突变）均被敲除的转基因小鼠提供了一个潜在有用的肿瘤发生模型，因为这些小鼠会迅速发生自发性肿瘤。为了确定p53基因敲除小鼠的肿瘤发生是否对实验操作敏感，评估了其对卡路里限制（CR；啮齿动物肿瘤的有效抑制剂）的肿瘤发生反应。在雄性纯合p53基因敲除小鼠和野生型同窝小鼠（每个治疗组28 - 30只）中监测肿瘤发生48周，这些小鼠自由采食（AL）或限制摄入AL碳水化合物卡路里摄入量的60%。与AL喂养的p53基因敲除小鼠（中位生存期 = 16周）相比，CR喂养的p53基因敲除小鼠（中位生存期 = 25周）肿瘤发生延迟且随后的死亡率降低（P = 0.0002）。在两种饮食处理下，野生型同窝小鼠在48周内的肿瘤发生和死亡率均<4%。在AL喂养或CR 4周后（每组5只），对p53基因敲除小鼠和野生型同窝小鼠的脾细胞进行细胞周期分析。p53基因敲除小鼠处于细胞周期S期的脾细胞百分比比野生型小鼠高3倍（P < 0.001），并且CR降低了p53基因敲除小鼠和野生型小鼠中S期脾细胞的百分比（P = 0.012）。这些数据表明，CR（可能通过细胞周期调节）可延迟具有肿瘤遗传易感性的p53基因敲除小鼠的肿瘤发生，并表明这些小鼠提供了一个非常有用的自发性肿瘤发生模型。
