Bearss D J, Subler M A, Hundley J E, Troyer D A, Salinas R A, Windle J J
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, TX 78284 USA.
Oncogene. 2000 Feb 21;19(8):1114-22. doi: 10.1038/sj.onc.1203275.
Several transgenic mouse tumor models were utilized to explore how specific genetic alterations affect the tumor cell response to chemotherapeutic agents in vivo. Specifically, MMTV-ras transgenic mice were interbred to p53 knock-out mice to create a model for assessing the role of p53 in chemotherapeutic responses. In addition, MMTV-ras tumors were compared to MMTV-myc and MMTV-ras/myc tumors. Mice of each genotype reproducibly develop mammary and/or salivary tumors, but tumor growth dynamics vary considerably between genotypes. MMTV-ras/p53-/- tumors exhibit higher S phase fractions than MMTV-ras/p53+/+ tumors, although both tumor types display very low apoptosis levels. In contrast, MMTV-myc tumors exhibit both high S phase fractions and spontaneous apoptosis levels. Tumor-bearing mice of each genotype were treated with either doxorubicin or paclitaxel, and effects on overall tumor growth, cell cycle distribution and apoptosis were evaluated. Surprisingly, neither agent efficiently induced apoptosis in any of the tumor models, including those with wildtype p53. Rather, tumor responses were mediated primarily by changes in cell cycle distribution. However, the spontaneous apoptosis levels did serve as a predictor of tumor growth response, in that only those tumors with high pretreatment apoptosis levels underwent significant regression following treatment with either agent.
利用几种转基因小鼠肿瘤模型来探究特定基因改变如何在体内影响肿瘤细胞对化疗药物的反应。具体而言，将MMTV-ras转基因小鼠与p53基因敲除小鼠杂交，以创建一个评估p53在化疗反应中作用的模型。此外，还将MMTV-ras肿瘤与MMTV-myc和MMTV-ras/myc肿瘤进行了比较。每种基因型的小鼠均可重复性地发生乳腺和/或唾液腺肿瘤，但不同基因型之间肿瘤生长动力学差异很大。MMTV-ras/p53-/-肿瘤的S期比例高于MMTV-ras/p53+/+肿瘤，尽管两种肿瘤类型的凋亡水平都非常低。相比之下，MMTV-myc肿瘤的S期比例和自发凋亡水平都很高。对每种基因型的荷瘤小鼠用阿霉素或紫杉醇进行治疗，并评估对总体肿瘤生长、细胞周期分布和凋亡的影响。令人惊讶的是，在任何肿瘤模型中，包括那些具有野生型p53的模型，这两种药物都不能有效地诱导凋亡。相反，肿瘤反应主要由细胞周期分布的变化介导。然而，自发凋亡水平确实可作为肿瘤生长反应的一个预测指标，因为只有那些预处理时凋亡水平高的肿瘤在用任何一种药物治疗后才会发生显著消退。
