Biochemical correlates of temozolomide sensitivity in pediatric solid tumor xenograft models.
Biochemical correlates of temozolomide sensitivity in pediatric solid tumor xenograft models.
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发表时间：
2000-03
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通讯作者：
D. Middlemas;C. Stewart;M. Kirstein;C. Poquette;H. Friedman;Peter J. Houghton;T. Brent
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作者：
D. Middlemas;C. Stewart;M. Kirstein;C. Poquette;H. Friedman;Peter J. Houghton;T. Brent
针对一组17个来自儿科实体瘤的异种移植物，评价了甲基化剂替莫唑胺的抗肿瘤活性。替莫唑胺经口给药。每日一次，连续5天，剂量水平为66 mg/kg。每21天重复治疗3个周期。肿瘤细胞系被分类为具有高、中等或低敏感性，分别通过完全响应、部分响应或稳定疾病来确定。总体而言，替莫唑胺在5个细胞系中诱导了完全缓解，在另外3个肿瘤细胞系中诱导了部分缓解，在47%的异种移植细胞系中获得了客观消退。替莫唑胺血浆全身暴露量分析表明，该剂量水平与患者达到的暴露量相关。通过免疫印迹法分析肿瘤中O 6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）和两种错配修复蛋白MLH-1和MSH-2的水平。归类为具有高或中等敏感性的肿瘤具有低或不可检测的MGMT，并表达可检测的MLH-1和MSH-2蛋白。归类为具有低敏感性的肿瘤具有（a）高MGMT或（B）低或不可检测的MGMT但缺乏MLH-1。还检查了p53与替莫唑胺反应之间的关系。在体外替莫唑胺没有诱导p53-能力NB-1643神经母细胞瘤细胞p21 cip 1。通过稳定表达反式显性阴性p53（NB 1643 p53 TDN）抑制NB 1643克隆中的p53功能并不赋予替莫唑胺耐药性。同样，肿瘤对替莫唑胺的敏感性与p53基因型或p53功能状态无关。这些结果表明，MGMT是替莫唑胺耐药的主要机制，但在没有MGMT的情况下，熟练的错配修复决定了对这种药物的敏感性。
The antitumor activity of the methylating agent temozolomide has been evaluated against a panel of 17 xenografts derived from pediatric solid tumors. Temozolomide was administered p.o. daily for five consecutive days at a dose level of 66 mg/kg. Courses of treatment were repeated every 21 days for three cycles. Tumor lines were classified as having high, intermediate, or low sensitivity, determined by complete responses, partial responses, or stable disease, respectively. Overall, temozolomide induced complete responses in five lines and partial responses in three additional tumor lines, giving objective regressions in 47% of xenograft lines. Analysis of temozolomide plasma systemic exposure indicated that this dose level was relevant to exposure achieved in patients. Tumors were analyzed by immunoblotting for levels of O6-methylguanine-DNA methyltransferase (MGMT) and two mismatch repair proteins, MLH-1 and MSH-2. Tumors classified as having high or intermediate sensitivity had low or undetectable MGMT and expressed detectable MLH-1 and MSH-2 proteins. Tumors classified as having low sensitivity had either (a) high MGMT or (b) low or undetectable MGMT but were deficient in MLH-1. The relationship between p53 and response to temozolomide was also examined. In vitro temozolomide did not induce p21cip1 in p53-competent NB-1643 neuroblastoma cells. Suppression of p53 function in NB1643 clones through stable expression of a trans dominant negative p53 (NB1643p53TDN) did not confer temozolomide resistance. Similarly, tumor sensitivity to temozolomide did not segregate with p53 genotype or p53 functional status. These results indicate that MGMT is the primary mechanism for temozolomide resistance, but in the absence of MGMT, proficient mismatch repair determines sensitivity to this agent.