Ozols R F, O'Dwyer P J, Hamilton T C
Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
Gynecol Oncol. 1993 Oct;51(1):90-6. doi: 10.1006/gyno.1993.1252.
Human ovarian cancer cell lines and relevant in vivo model systems have been used to identify mechanisms of resistance associated with alkylating agents and platinum compounds. Drug resistance in ovarian cancer is multifactorial and it is probable that additional mechanisms than those already identified may be responsible for clinical drug resistance. Presently drug transport, increased inactivation in the cytosol, increased repair of damaged DNA, and alterations in signal transduction pathways have been shown to account for resistance of alkylating agents and platinum compounds. Clinical trials have been initiated with agents such as buthionine-sulfoximine, an inhibitor of glutathione biosynthesis which decreases the ability of resistant cells to inactivate platinum compounds prior to their interaction with DNA. In a phase I trial, it has been demonstrated that glutathione levels can be depleted both in normal tissues and tumor biopsies from drug-resistant ovarian cancer patients. Additional clinical trials are needed to determine the effect that glutathione reduction has upon response rate to alkylating agents and platinum compounds. Ultimately, successful modulation of drug resistance may require a combination of agents which inhibit multiple critical biochemical sites. In addition, an understanding of the mechanisms associated with antineoplastic drug resistance may lead to novel therapeutic strategies aimed at preventing the emergence of clinically relevant resistance.
人类卵巢癌细胞系和相关的体内模型系统已被用于确定与烷化剂和铂类化合物相关的耐药机制。卵巢癌的耐药是多因素的，很可能除了已确定的机制外，还有其他机制导致临床耐药。目前已表明，药物转运、胞浆内失活增加、受损DNA修复增加以及信号转导途径改变可解释烷化剂和铂类化合物的耐药性。已开始使用诸如丁硫氨酸 - 亚砜胺等药物进行临床试验，丁硫氨酸 - 亚砜胺是谷胱甘肽生物合成的抑制剂，可降低耐药细胞在铂类化合物与DNA相互作用之前使其失活的能力。在一项I期试验中，已证明耐药卵巢癌患者的正常组织和肿瘤活检组织中的谷胱甘肽水平均可降低。需要进行更多的临床试验来确定降低谷胱甘肽对烷化剂和铂类化合物反应率的影响。最终，成功调节耐药性可能需要联合使用抑制多个关键生化位点的药物。此外，了解与抗肿瘤药物耐药性相关的机制可能会带来旨在预防临床相关耐药性出现的新治疗策略。
