Muggia F M, Los G
University of Southern California, Kenneth Norris Jr. Cancer Center, Los Angeles 90033.
Stem Cells. 1993 May;11(3):182-93. doi: 10.1002/stem.5530110304.
Platinum compounds are universally recognized as one of the most important classes of chemotherapeutic agents for the treatment of cancer. Emergence of resistance to cisplatin has appeared, however, to be a major prognostic factor of adverse outcome in the otherwise most sensitive of malignancies: testicular and ovarian cancers. After a decade of testing both systemic and regional dose-intensification of cisplatin and its analog carboplatin--which is more amenable to dose escalation with cytokines and bone marrow progenitor cell support--a plateau is apparent even in sensitive tumor types beyond which additional dose escalations do not appreciably increase response. Laboratory work searching for causes of intrinsic and acquired resistance, providing early indication of drug sensitivity, and developing strategies for restoring or overcoming resistance is ongoing and is guiding clinical studies and drug development. Causes of cellular resistance to platinums are complex and include decreased drug accumulation, increased detoxification, increased repair of DNA-platinum adducts, and increased tolerance of DNA lesions. Clinical trials are already ongoing regarding strategies involving protection of specific toxicities, decreasing intracellular glutathione (by buthionine sulfoximine), decreasing DNA repair, and introducing new analogs that are able to overcome certain forms of platinum resistance.
铂类化合物被公认为是治疗癌症最重要的一类化疗药物。然而，顺铂耐药的出现已成为原本最敏感的恶性肿瘤（睾丸癌和卵巢癌）不良预后的主要预测因素。在对顺铂及其类似物卡铂进行了十年的全身和区域剂量强化试验之后——卡铂更易于通过细胞因子和骨髓祖细胞支持进行剂量递增——即使在敏感肿瘤类型中也出现了一个平台期，超过这个平台期进一步增加剂量并不能显著提高反应率。寻找内在和获得性耐药原因、提供药物敏感性早期指标以及制定恢复或克服耐药策略的实验室工作正在进行中，并指导着临床研究和药物开发。细胞对铂类耐药的原因很复杂，包括药物蓄积减少、解毒增加、DNA-铂加合物修复增加以及对DNA损伤的耐受性增加。关于涉及保护特定毒性、降低细胞内谷胱甘肽（通过丁硫氨酸亚砜胺）、减少DNA修复以及引入能够克服某些形式铂耐药的新类似物的策略的临床试验已经在进行。
