Matzinger S A, Crist K A, Stoner G D, Anderson M W, Pereira M A, Steele V E, Kelloff G J, Lubet R A, You M
Medical College of Ohio, Toledo 43699, USA.
Carcinogenesis. 1995 Oct;16(10):2487-92. doi: 10.1093/carcin/16.10.2487.
The purpose of this study was to evaluate the effects of the loss of a p53 allele and phenethyl isothiocyanate (PEITC) pre-treatment on the tumorigenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and K-ras mutation frequency in a hybrid mouse model. Male TSG-p53 'knock-out' mice were bred with A/J female mice to produce (A/J x TSG-p53) F1 mice either homozygous (p53+/+) or heterozygous (p53+/-) for p53 alleles. These mice, together with female A/J mice, were treated at 6-8 weeks of age with NNK or dosed with PEITC prior to administration of NNK. The A/J mice treated with NNK had a 100% incidence of lung tumors, with 9.7 +/- 3.4 tumors/mouse. A/J mice pre-treated with PEITC prior to NNK administration had 3.5 +/- 2.1 lung tumors/animal, although the incidence remained at 100%. In (A/J x TSG-p53) F1 mice with either the p53(+/-) or p53(+/+) genotype PEITC pre-treatment significantly decreased tumor incidence (100 to 40 and 36%, respectively) and multiplicity (2.0 +/- 0.5 to 0.5 +/- 0.4 and 2.1 +/- 0.5 to 0.5 +/- 0.4, respectively), indicating that PEITC is an effective chemopreventive agent in both A/J mice and (A/J x TSG-p53) F1 mice. Analysis of lung tumor DNA from A/J mice treated with NNK or NNK/PEITC indicated that 15 of 17 (88%) and 20 of 23 (87%) of the tumors, respectively, contained G-->A transitions at the second base of codon 12 in the K-ras gene. Similarly, in lung tumors from (A/J x TSG-p53) F1 mice treated with NNK or NNK/PEITC 29 of 30 (96%) and 9 of 10 (90%), respectively contained G-->A transitions at the second base of codon 12 of the K-ras gene. No mutations of the p53 gene were found in any of the tumors analyzed, suggesting minimal involvement of this gene in the development of lung adenomas. These data indicate that absence of a p53 allele in (A/J x TSG-p53) F1 mice does not alter the incidence or multiplicity of NNK-induced lung tumors and that PEITC inhibition of NNK tumorigenesis does not affect the frequency or spectrum of K-ras gene mutations found consistently with NNK carcinogenesis.
本研究旨在评估在杂交小鼠模型中，p53等位基因缺失和异硫氰酸苯乙酯（PEITC）预处理对4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）致瘤性及K-ras突变频率的影响。将雄性TSG-p53“基因敲除”小鼠与A/J雌性小鼠杂交，以产生p53等位基因纯合（p53+/+)或杂合（p53+/-）的（A/J×TSG-p53）F1小鼠。这些小鼠与雌性A/J小鼠在6 - 8周龄时接受NNK处理，或在给予NNK之前给予PEITC。接受NNK处理的A/J小鼠肺肿瘤发生率为100%，每只小鼠有9.7±3.4个肿瘤。在给予NNK之前用PEITC预处理的A/J小鼠，每只动物有3.5±2.1个肺肿瘤，尽管发生率仍为100%。在p53(+/-)或p53(+/+)基因型的（A/J×TSG-p53）F1小鼠中，PEITC预处理显著降低了肿瘤发生率（分别从100%降至40%和36%）和肿瘤数量（分别从2.0±0.5降至0.5±0.4和从2.1±0.5降至0.5±0.4），这表明PEITC在A/J小鼠和（A/J×TSG-p53）F1小鼠中都是一种有效的化学预防剂。对接受NNK或NNK/PEITC处理的A/J小鼠肺肿瘤DNA分析表明，17个肿瘤中的15个（88%）和23个肿瘤中的20个（87%），在K-ras基因第12密码子的第二个碱基处发生了G→A转换。同样，在接受NNK或NNK/PEITC处理的（A/J×TSG-p53）F1小鼠的肺肿瘤中，30个肿瘤中的29个（96%）和10个肿瘤中的9个（90%），在K-ras基因第12密码子的第二个碱基处也发生了G→A转换。在分析的任何肿瘤中均未发现p53基因的突变，这表明该基因在肺腺瘤的发生中参与程度极小。这些数据表明，（A/J×TSG-p53）F1小鼠中p53等位基因的缺失不会改变NNK诱导的肺肿瘤的发生率或数量，并且PEITC对NNK致瘤作用的抑制不会影响与NNK致癌作用一致的K-ras基因突变频率或谱。
