MECHANISMS OF DRUG RESISTANCE IN SOFT TISSUE SARCOMA

在这个更新项目中，作为我们努力改善软组织肉瘤患者治疗的一部分，我们计划利用过去5-6年获得的信息，开始根据肿瘤的基因型和表型选择特定治疗的患者。本计划涉及本奖助金中其他计划的密切合作与互动。项目一将有机会获得足够的新鲜肿瘤样本进行相关研究并启动患者试验。STS细胞系和新鲜肿瘤样本的分析是与项目II和项目（滑膜细胞肉瘤）密切合作进行的。具体来说，我们计划继续评估特定的E2F形式（E2F2, E2F4）作为化疗靶基因（胸腺苷酸合成酶，二氢叶酸还原酶，核糖核苷酸还原酶胸腺嘧啶激酶）的转录调节因子，以及使用靶向这些酶的药物上调这些转录因子对化学敏感性的影响。与C. Cordon-Cardo博士合作，我们将对某些化疗药物的靶基因和软组织肉瘤细胞系（n=12）中参与细胞周期控制的基因表达进行详细分析，并将这些测量结果与化疗敏感性联系起来。同时，我们将在新鲜的STS样本中进行类似的实验，并开发针对特定剖面的处理方法。我们初步制定了四种不同的治疗方案；多柔宾治疗缺乏功能性pRb（有或没有突变型p53）的肿瘤，这些肿瘤也是MDR和MPR阴性的；低水平TS患者的雷利曲（ralitrexed）；对于缺乏甲硫腺苷磷酸化酶（与p16缺失相关）的患者，l -丙氨酸加5-脱氧腺苷或不加5-脱氧腺苷；对于叶酸载体表达水平低的患者，三甲氨蝶呤加伴随的亚叶酸钙。

In this renewal project as part of our effort to improve the treatment of patients with soft tissue sarcoma, we plan to utilize the information obtained in the past 5-6 years, to begin to select patients for specific treatments, based upon the genotype and phenotype of the tumor. This project involves the close collaboration and interaction of the other projects in this grant. Project I will afford the opportunity to obtain a sufficient member of fresh tumor samples for correlative studies and initiate patient trials. Analysis of STS cell lines and fresh tumor samples are carried out in close collaboration with project II, and project (synovial cell sarcomas). Specifically, we plan to continue to evaluate specific E2F forms (E2F2, E2F4) as transcriptional regulators for chemotherapeutic target genes (thymidylate synthase, dihydrofolate reductase, ribonucleotide reductase thymidine kinase), and the effects of up-regulation of these transcription factors on chemosensitivity using drugs that target these enzymes. In collaboration with Dr. C. Cordon-Cardo, we will carry out a detailed analysis of target genes for certain chemotherapeutic agents, and expression of genes involved in cell cycle control in soft tissue sarcoma cell lines (n=12), and will correlate these measurements with chemosensitivity. We will in parallel, carry out similar experiments in fresh STS samples and develop treatments that target a specific profile. We have tentatively generated four different treatment regimens; doxorubin treatment for tumors lacking functional pRb (with or without mutant p53), that also are MDR and MPR negative; ralitrexed )Tomudex ) treatment for patients with low levels of TS; L-alanosine with or without 5-deoxyadenosine for patients lacking meththioadenosine phosphorylase (associated with p16 deletions), and trimetrexate plus concomitant leucovorin, for patients demonstrating low levels of reduce folate carrier expression.