Hudson Laurie G, Cook Linda S, Grimes Martha M, Muller Carolyn Y, Adams Sarah F, Wandinger-Ness Angela
Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
Department of Internal Medicine, Division of Epidemiology and Biostatistics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
Cancers (Basel). 2019 Jul 24;11(8):1049. doi: 10.3390/cancers11081049.
Cytoreductive surgery and chemotherapy are cornerstones of ovarian cancer treatment, yet disease recurrence remains a significant clinical issue. Surgery can release cancer cells into the circulation, suppress anti-tumor immunity, and induce inflammatory responses that support the growth of residual disease. Intervention within the peri-operative window is an under-explored opportunity to mitigate these consequences of surgery and influence the course of metastatic disease to improve patient outcomes. One drug associated with improved survival in cancer patients is ketorolac. Ketorolac is a chiral molecule administered as a 1:1 racemic mixture of the S- and R-enantiomers. The S-enantiomer is considered the active component for its FDA indication in pain management with selective activity against cyclooxygenase (COX) enzymes. The R-enantiomer has a previously unrecognized activity as an inhibitor of Rac1 (Ras-related C3 botulinum toxin substrate) and Cdc42 (cell division control protein 42) GTPases. Therefore, ketorolac differs from other non-steroidal anti-inflammatory drugs (NSAIDs) by functioning as two distinct pharmacologic entities due to the independent actions of each enantiomer. In this review, we summarize evidence supporting the benefits of ketorolac administration for ovarian cancer patients. We also discuss how simultaneous inhibition of these two distinct classes of targets, COX enzymes and Rac1/Cdc42, by S-ketorolac and R-ketorolac respectively, could each contribute to anti-cancer activity.
减瘤手术和化疗是卵巢癌治疗的基石，但疾病复发仍然是一个重大的临床问题。手术会将癌细胞释放到循环系统中，抑制抗肿瘤免疫，并引发支持残留疾病生长的炎症反应。围手术期进行干预是一个尚未充分探索的机会，可以减轻手术的这些后果，并影响转移性疾病的进程，从而改善患者的预后。一种与癌症患者生存率提高相关的药物是酮咯酸。酮咯酸是一种手性分子，以S-和R-对映体的1:1外消旋混合物形式给药。S-对映体因其在疼痛管理方面的FDA适应症以及对环氧合酶（COX）酶的选择性活性而被认为是活性成分。R-对映体具有一种以前未被认识的活性，即作为Rac1（Ras相关的C3肉毒杆菌毒素底物）和Cdc42（细胞分裂控制蛋白42）GTP酶的抑制剂。因此，由于每种对映体的独立作用，酮咯酸作为两种不同的药理实体发挥作用，这与其他非甾体抗炎药（NSAIDs）不同。在本综述中，我们总结了支持酮咯酸给药对卵巢癌患者有益的证据。我们还讨论了分别由S-酮咯酸和R-酮咯酸同时抑制这两类不同的靶点COX酶和Rac1/Cdc42，如何各自有助于抗癌活性。
