Genetic determinants of response to chemotherapy in transgenic mouse mammary and salivary tumors
Genetic determinants of response to chemotherapy in transgenic mouse mammary and salivary tumors
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DOI：
10.1038/sj.onc.1203275
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发表时间：
2000-02-21
期刊：
影响因子：
8
通讯作者：
Windle, JJ
中科院分区：
文献类型：
--
作者：
Bearss, DJ;Subler, MA;Windle, JJ
利用几种转基因小鼠肿瘤模型来探索特定的遗传改变如何影响体内肿瘤细胞对化疗剂的反应。具体地，将MMTV-ras转基因小鼠与p53敲除小鼠杂交以创建用于评估p53在化疗反应中的作用的模型。此外，将MMTV-ras肿瘤与MMTV-myc和MMTV-ras/myc肿瘤进行比较。每种基因型的小鼠可重复地发展乳腺和/或唾液腺肿瘤，但肿瘤生长动力学在基因型之间变化很大，MMTV-ras/p53（-/-）肿瘤表现出比MMTV-ras/p53（+/+）肿瘤更高的S期分数，尽管两种肿瘤类型显示出非常低的凋亡水平。相比之下，MMTV-myc肿瘤表现出高S期分数和自发凋亡水平。每种基因型的荷瘤小鼠仅用多柔比星或紫杉醇治疗，并评价对总体肿瘤生长、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，包括野生型p53的那些模型，两种药物都没有有效诱导细胞凋亡。相反，肿瘤反应主要由细胞周期分布的变化介导。然而，自发性凋亡水平确实可以作为肿瘤生长反应的预测因子，因为只有那些具有高预处理凋亡水平的肿瘤在用任一种药物治疗后发生显著消退。
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 mere 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.