INCREASED EXPRESSION OF STRESS-INDUCED GENES IN CHEMORESISTANT TUMOR CELLS

癌症化疗的一个主要问题是耐药细胞的出现， 细胞化疗耐药可能是多种机制共同作用的结果 包括改变药物的摄取/排泄，增加药物的失活， 以及改变宿主反应，例如增加DNA修复。中概述的 项目编号ZOI CM 06380-03 RO，我们已经分离出多种哺乳动物 编码由DNA损伤特异性诱导的转录物的cDNA克隆。 我们已经开始了各种人类肿瘤细胞系的研究， 已经选择了对顺式二氯二氨铂（DDP）的抗性， 氮芥（HN 2）或其它烷基化剂。我们最初的研究 包括确定不同压力诱导的转录水平， 与它们的亲本细胞相比， 正常灵敏度的线路。过度表达的几个例子 我们在DDP和烷化剂耐药细胞中的某些DDI转录物 例如，在gadd 33 RNA的情况下， 在DDP、美法仑和HN 2耐药的人中， 肿瘤细胞系以及MNNG抗性中国仓鼠细胞系。 DDIA 18 mRNA在某些细胞中显著升高， 耐药人卵巢细胞系。这些研究表明， 某些DNA损伤诱导基因的过度表达可能 在化疗耐药性中发挥作用。

A major problem in cancer chemotherapy is the emergence of drug-resistant cells. Chemotherapy-resistance is probably due to multiple mechanisms including altered uptake/excretion of drug, increased inactivation of drug, and altered host response such as increased DNA repair. As outlined in project number ZOI CM 06380-03 RO, we have isolated a variety of mammalian cDNA clones which code for transcripts specifically induced by DNA damage. We have initiated studies with a variety of human tumor cell lines which have been selected for resistance to cis-Pt diamminedichloride (DDP), nitrogen mustard (HN2), or other alkylating agents. Our initial studies have involved determining the level of different stress-induced transcripts in these chemoresistant tumor cell lines compared to their parent cell lines with normal sensitivity. Several examples of over-expression of certain of our DDI transcripts in DDP and alkylating agent resistant cells have been found. For example, in the case of gadd33 RNA, this transcript was constitutively elevated in both DDP, melphalan, and HN2 resistant human tumor cell lines and also in a MNNG resistant Chinese hamster cell line. DDIA18 mRNA was found to be substantially elevated in certain chemoresistant human ovarian cell lines. These studies raise the important possibility that overexpression of certain DNA-damage-inducible genes may play a role in chemotherapy resistance.