METALLOTHIONEIN AND CYTOTOXIC DRUG RESISTANCE

这一奖项的目的是为了发展一位内科科学家 癌症药理学。这位候选人已经证明了他有潜力 致力于临床泌尿外科肿瘤学，并致力于学术 职业生涯。然而，他缺乏正规的基础科学培训。赞助商是 公认的癌症研究人员，有既定的培训记录 基础科学环境中的医生。拟议中的调查 金属硫蛋白(MT)与细胞毒耐药寻求培养 分子生物学、药理学和医学领域的临床医生 实验疗法和寻找战胜肿瘤的新策略 对化疗有抵抗力。 这项研究计划旨在调查MT在 对顺铂(CDDP)及相关抗癌药物产生耐药性。 CDDP对多种人类肿瘤有效，据信通过 在染色体DNA中形成共价交联链。不幸的是， 肿瘤细胞的耐药性发展限制了治疗的有效性 CDDP。MT，一种富含半胱氨酸的蛋白质，可保护细胞免受重压 金属毒性，是调节细胞反应的一个重要候选因素 细胞毒性药物，尤指那些与巯基起反应的药物。我们会 用酶法检测耐药细胞系MT的升高 使用抗MT抗体的酶联免疫吸附试验(ELISA)。自.以来 人类MT以几种异构体形式存在，单抗是特异的 将开发出每种人类亚型，并将使用酶联免疫吸附试验检测 如果耐药细胞株在任何特定的亚型中表现出增加 Mt.Mt.此外，对cDDP的敏感性将在以下细胞中确定 MT水平由已建立的MT诱导剂操纵。过载的机制 MT的表达将通过表征MT基因的拷贝数来研究， MT的信使核糖核酸水平和信息稳定性。最后，mRNA和蛋白质 将测定患者组织样本中的MT水平 泌尿系统恶性肿瘤评估MT是否影响对cDDP和 CDDP是否改变人肿瘤组织MT的表达。 匹兹堡大学特别适合 肿瘤学内科科研人员的发展 匹兹堡癌症研究所最近被授予癌症中心 美国国立卫生研究院提供的三年资助。

The purpose of this award is the development of a physician scientist in cancer pharmacology. The candidate has demonstrated a potential to contribute to clinical urologic oncology and is committed to an academic career. However, he lacks formal basic science training. The sponsor is a recognized cancer researcher with an established record for training physicians in a basic science environment. The proposed investigation of metallothionein (MT) and cytotoxic drug resistance seeks to train a clinician in the discipline of molecular biology, pharmacology, and experimental therapeutics and to identify new strategies to overcome tumor resistance to chemotherapy. The research proposal is designed to investigate the role of MT in conferring resistance to cis-platin (cDDP) and related anti-cancer agents. cDDP is active against a variety of human tumors and is believed to act by forming covalent cross links in chromosomal DNA. Unfortunately, the development of resistance by tumor cells limits the therapeutic usefulness of cDDP. MT, a cysteine rich protein that protects cells against heavy metal toxicity, is an important candidate to modulate cellular response to cytotoxic drugs, especially those reactive with sulfhydryl groups. We will examine the elevation of MT in drug resistant cell lines utilizing enzyme linked immunosorbent assay (ELISA) using antibodies against MT. Since human MT exists in several isomeric forms, monoclonal antibodies specific for each human isoform will be developed and ELISA will be used to examine if drug-resistant cell lines exhibit increases in any particular isoform of MT. In addition, the sensitivity to cDDP will be determined in cells with MT levels manipulated by established inducers of MT. The mechanism of over expression of MT will be studied by characterizing the MT gene copy number, mRNA level and stability of message of MT. Finally, mRNA and protein levels of MT will be determined in tissue samples from patients with urologic malignancy to evaluate if MT influences responsiveness to cDDP and whether cDDP alters human tumor expression of MT. The University of Pittsburgh is particularly well suited for the development of physician investigators in oncology because of its Pittsburgh Cancer Institute which was recently awarded a Cancer Center Support Grant for three years from the NIH.