CYCLOSPORINE A AND SIGNAL TRANSDUCTION

多效性耐药的特征是细胞内 膜性能 事实表明，某些 化疗药物在一定水平上发挥抗肿瘤作用 膜。 环孢素A（CsA）分配到磷脂中 囊泡和干扰质膜磷脂 新陈代谢. 它也被证明可以减少运动 自由的膜脂和去角质质膜 在小鼠淋巴细胞中的潜力。 其总体目标是 建议是了解CsA对信号的影响 转导途径使用肿瘤（敏感和 多效性耐药）和正常T和EBV诱导的B细胞 线 本研究的具体目的是：（1）比较血浆 敏感T和B白血病细胞系的膜电位， 其相应的耐药亚系，以及在T和B细胞中 来源于正常淋巴细胞的细胞系。 细胞膜电位 将使用FACS用DiOC 5染料进行研究。 (2)审查 CsA对三磷酸肌醇生成的影响 耐药和敏感白血病细胞系以及T和B细胞系 来源于正常的淋巴细胞。 (3)研究体外直接 CsA对蛋白质活化和转运的影响 肿瘤及正常淋巴细胞T、B中蛋白激酶C 细胞系 还将进行研究，以审查 CsA对PMA诱导的活化和易位的影响将是 通过免疫沉淀和间接 免疫荧光，使用同种抗体对PKC。 (4)到 检测CsA对P- 180. 研究将有助于理解 CsA对淋巴细胞活化早期的作用机制 以及CsA纠正多效性药物的机制 肿瘤细胞的耐药性。

Pleiotropic drug resistance is characterized by alterations in cell membrane properties. It has been shown that certain chemotherapeutic agents exert antineoplastic effect at the level of membrane. Cyclosporine A (CsA) partitions into phospholipid vesicles and interferes with plasma membrane phospholipid metabolism. It has also been shown to decrease the motional freedom of membrane lipids and to depolarize plasma membrane potentials in murine lymphoctyes. The overall aim of this proposal is to understand the effects of CsA on signal transduction pathway using both neoplastic (sensitive and pleiotropic drug resistant) and normal T and EBV-induced B cell lines. The specific aims of the study are: (1) To compare plasma membrane potentials in sensitive T and B leukemia cell lines and their corresponding drug resistant sublines, and in T and B cells lines derived from normal lymphocytes. The membrane potentials will be studied with DiOC5 dye using FACS. (2) To examine the effect of CsA on the generation of inositol trisphosphate in resistant and sensitive leukemic cell lines and T and B cell lines derived from normal lymphocytes. (3) To study the in vitro direct effect of CsA on the activation and translocation of protein kinase C (PKC) in tumor and normal lymphocyte-derived T and B cells lines. Studies will also be done to examine regulatory role of CsA on PMA-induced activation and translocation will be measured by immunoprecipitation and indirect immunofluorescence, using an alloantibody against PKC. (4) To examine the effect of CsA on membrane phosphorylation of P- 180. The studied would help in the understanding of the mechanisms of CsA on the early steps of lymphocyte activation and the mechanisms by which CsA corrects the pleiotropic drug resistance in neoplastic cells.