BIOMODULATION OF CHEMORESISTANCE IN MELANOMA

该计划的重点是研究化学敏感性的调制 通过生物疗法治疗人类恶性黑色素瘤 三个项目重点 在一项随机临床试验中， 反应率）的序贯生物化疗方案正在测试中。 的 生物治疗增加黑色素瘤药物反应的机制是 不清楚 本项目的目标是使用实验模型 以更好地了解时间和剂量反应 通过IL-2调节细胞耐药性的关系， IFN α和肿瘤巨噬细胞在这些反应中的作用。 我们 工作假设是巨噬细胞衍生的氧化剂调节 人黑素瘤细胞对顺铂的敏感性。 隐含在这个 一种假设是，这种氧化剂可以增加或减少药物 敏感性取决于试剂的顺序、剂量和时间表。 在 用人黑色素瘤异种移植模型进行的体内研究， 细胞因子生物治疗诱导的化疗增敏作用的时间方面， 化学保护将通过体外研究来补充，以确定 肿瘤巨噬细胞来源的氧化剂（H_2O_2，O_2-，NO）在肿瘤细胞凋亡中的作用 克隆性黑色素瘤细胞中顺铂敏感性的调节。 我们 还将确定相关的细胞因子和抗氧化剂途径， 影响细胞因子介导的细胞化学敏感性变化。 以来 我们的IRPG的工作假设是，氧化应激可以改变 肿瘤细胞修复顺铂诱导的DNA损伤的能力，我们将使用 原子吸收光谱法测定氧化应激的影响 顺铂在肿瘤细胞DNA中的蓄积和滞留。 我们 这些研究将与格里姆博士的R 0 -1项目相互补充和交叉 研究生物治疗对巨噬细胞功能的影响， 血浆脂质过氧化反应和Ali-Osman博士的研究项目 氧化应激对临床药物敏感性的影响 以及顺式铂-DNA链间交联的修复。 我们的研究 将导致更好地理解生物治疗的相互作用， 化疗，并将提供新的更多的设计见解 治疗恶性黑色素瘤的有效方法，以及其他 更普遍的癌症。

The focus of the program is to study the modulation of chemosensitivity by biotherapy in human malignant melanoma. The 3 projects are focused around a randomized clinical trial in which a promising (greater than 50% response rate) sequential biochemotherapy regimen is being tested. The mechanisms by which biotherapy increase drug response in melanoma are unclear. The goal of the present project is to use experimental models of human melanoma to better understand the time and dose response relationships for the modulation of cellular drug resistance by IL-2 and IFNalpha and the role of tumor macrophages in these responses. Our working hypothesis is that macrophage derived oxidants modulate the sensitivity of human melanoma cells to cisPlatin. Implicit in this hypothesis is that such oxidants may either increase or decrease drug sensitivity depending on the sequence, dose and schedule of agents. In vivo studies with xenograft models of human melanoma to identify the temporal aspects of cytokine biotherapy induced chemosensitization and chemoprotection will be complemented by in vitro studies to determine the role of resident tumor macrophage derived oxidants (H2O2, O2-,NO) in the modulation of cisPlatin sensitivity in clonogenic melanoma cells. We will also identify relevant cytokine and anti-oxidant pathways which may affect cytokine mediated changes in cellular chemosensitivity. Since the working hypothesis for our IRPG is that oxidant stress can alter the ability of tumor cells to repair cisPlatin induce DNA injury, we will use atomic absorption spectroscopy to determine the effect of oxidant stress on the accumulation and retention of cisPlatin in tumor cell DNA. Our studies will complement and interdigitate with Dr. Grimm's R0-1 project to investigate the effects of biotherapy on macrophage functions and plasma lipid peroxidation and with Dr. Ali-Osman's project to investigate the effects of oxidant stress on drug sensitivity in clinical material and the repair of cis-Platin-DNA interstrand crosslinks. Our studies will lead to a better understanding of the interaction of biotherapy and chemotherapy and will provide insights for the design of new more efficacious approaches for the treatment of malignant melanoma, and other more prevalent cancers.