Kolaja K L, Bunting K A, Klaunig J E
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis 46202, USA.
Carcinogenesis. 1996 Aug;17(8):1657-64. doi: 10.1093/carcin/17.8.1657.
The effects of dietary restriction on the growth of hepatic focal lesions in phenobarbital (PB) promoted mice were examined. Dietary restriction which can inhibit many age-related diseases in rodents including hepatic cancer also decreases cell proliferation and increases apoptosis in the liver. In contrast, PB, a non-genotoxic rodent hepatocarcinogen, enhances the growth of hepatic focal lesions in mice and rats by increasing cell proliferation and inhibiting apoptosis. The present study examined the impact of dietary restriction on PB-induced hepatic tumor promotion. Focal lesions were produced by diethylnitrosamine (DEN) treatment (35 mg DEN/kg body weight injections, twice per week for 8 weeks). After lesions were produced, mice were placed into one of the following four groups: NIH-07 control diet/no PB (group 1); NIH-07 diet/500 mg PB per liter of drinking water (group 2); dietary restricted NIH-07 diet/no PB (group 3); and dietary restricted NIH-7 diet/ 500 mg PB per liter of drinking water (group 4). In this study, PB (500 mg/l) treatment to ad libitum-fed mice (group 2) enhanced focal lesion volume, number, and labeling index compared with group 1. In addition, PB treatment (group 2) inhibited apoptosis in normal and focal hepatocytes compared with untreated control mice (group 1). In contrast, in dietary restricted mice treated with PB (group 4) a significantly lower focal lesion volume, number and labeling index were seen compared with the ad libitum-fed/PB treatment group (group 2). PB treatment in dietary restricted mice (group 4) did not inhibit focal apoptosis, in fact, the incidence of focal apoptosis was increased in these mice compared with ad libitum and PB-treated mice (group 2). In dietary restricted mice treated with PB (group 4), the ability of PB to promote the growth of preneoplastic focal lesions was inhibited. These results show that dietary restriction can ablate the tumor promotional effects of PB in hepatic focal lesions and suggest that inhibition of focal lesion DNA synthesis and enhancement of apoptosis may be a mechanism for this effect.
研究了饮食限制对苯巴比妥（PB）诱导的小鼠肝脏局灶性病变生长的影响。饮食限制可抑制啮齿动物包括肝癌在内的许多与年龄相关的疾病，同时也会减少肝脏中的细胞增殖并增加细胞凋亡。相比之下，PB作为一种非遗传毒性的啮齿动物肝癌致癌物，通过增加细胞增殖和抑制凋亡来促进小鼠和大鼠肝脏局灶性病变的生长。本研究考察了饮食限制对PB诱导的肝脏肿瘤促进作用的影响。通过二乙基亚硝胺（DEN）处理（按35mg DEN/kg体重注射，每周两次，共8周）产生局灶性病变。病变产生后，将小鼠分为以下四组之一：NIH-07对照饮食/无PB（第1组）；NIH-07饮食/每升饮用水含500mg PB（第2组）；饮食限制的NIH-07饮食/无PB（第3组）；以及饮食限制的NIH-7饮食/每升饮用水含500mg PB（第4组）。在本研究中，与第1组相比，给予自由摄食小鼠PB（500mg/l）处理（第2组）可增加局灶性病变体积、数量和标记指数。此外，与未处理的对照小鼠（第1组）相比，PB处理（第2组）可抑制正常和局灶性肝细胞中的凋亡。相比之下，在给予PB处理的饮食限制小鼠（第4组）中，与自由摄食/PB处理组（第2组）相比，局灶性病变体积、数量和标记指数显著降低。给予饮食限制小鼠PB处理（第4组）并未抑制局灶性凋亡，事实上，与自由摄食且给予PB处理的小鼠（第2组）相比，这些小鼠的局灶性凋亡发生率有所增加。在给予PB处理的饮食限制小鼠（第4组）中，PB促进癌前局灶性病变生长的能力受到抑制。这些结果表明，饮食限制可消除PB在肝脏局灶性病变中的肿瘤促进作用，并提示抑制局灶性病变DNA合成和增强凋亡可能是产生这种作用的一种机制。
