title: A Novel Pharmacologic Activity of Ketorolac for Therapeutic Benefit in Ovarian Cancer Patients.
abstract: OBJECTIVE
  We previously identified the R-enantiomer of ketorolac as an inhibitor of the Rho-family GTPases Rac1 and Cdc42. Rac1 and Cdc42 regulate cancer-relevant functions, including cytoskeleton remodeling necessary for tumor cell adhesion and migration. This study investigated whether administration of racemic (R,S) ketorolac after ovarian cancer surgery leads to peritoneal distribution of R-ketorolac, target GTPase inhibition in cells retrieved from the peritoneal cavity, and measureable impact on patient outcomes.
  
  
  METHODS
  Eligible patients had suspected advanced-stage ovarian, fallopian tube or primary peritoneal cancer. Secondary eligibility was met when ovarian cancer was confirmed and optimally debulked, an intraperitoneal port was placed, and there were no contraindications for ketorolac administration. R- and S-ketorolac were measured in serum and peritoneal fluid, and GTPase activity was measured in peritoneal cells. A retrospective study correlated perioperative ketorolac and ovarian cancer-specific survival in ovarian cancer cases.
  
  
  RESULTS
  Elevated expression and activity of Rac1 and Cdc42 was detected in ovarian cancer patient tissues, confirming target relevance. Ketorolac in peritoneal fluids was enriched in the R-enantiomer and peritoneal cell GTPase activity was inhibited after ketorolac administration when R-ketorolac was at peak levels. After adjusting for age, AJCC stage, completion of chemotherapy, and neoadjuvant therapy, women given perioperative ketorolac had a lower hazard of death (HR, 0.30; 95% confidence interval, 0.11-0.88).
  
  
  CONCLUSIONS
  Ketorolac has a novel pharmacologic activity conferred by the R-enantiomer and R-ketorolac achieves sufficient levels in the peritoneal cavity to inhibit Rac1 and Cdc42, potentially contributing to the observed survival benefit in women who received ketorolac.
authors.affiliation: Department of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico. Cancer Center, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Yuna
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, New Mexico. SRKenney@salud.unm.edu.
authors.forename: S Ray
authors.initials: SR
authors.lastname: Kenney
authors.affiliation: Cancer Center, University of New Mexico, Albuquerque, New Mexico. Division of Epidemiology, Biostatistics, and Preventive Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.
authors.forename: Linda
authors.initials: L
authors.lastname: Cook
authors.affiliation: Cancer Center, University of New Mexico, Albuquerque, New Mexico. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of New Mexico School of Medicine, Albuquerque, New Mexico.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Adams
authors.affiliation: Cancer Center, University of New Mexico, Albuquerque, New Mexico. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of New Mexico School of Medicine, Albuquerque, New Mexico.
authors.forename: Teresa
authors.initials: T
authors.lastname: Rutledge
authors.affiliation: Department of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico.
authors.forename: Elsa
authors.initials: E
authors.lastname: Romero
authors.affiliation: Cancer Center, University of New Mexico, Albuquerque, New Mexico. Division of Translational Informatics, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.
authors.forename: Tudor I
authors.initials: TI
authors.lastname: Oprea
authors.affiliation: Department of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico. Cancer Center, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Larry A
authors.initials: LA
authors.lastname: Sklar
authors.affiliation: Cancer Center, University of New Mexico, Albuquerque, New Mexico. Division of Epidemiology, Biostatistics, and Preventive Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.
authors.forename: Edward
authors.initials: E
authors.lastname: Bedrick
authors.affiliation: Cancer Center, University of New Mexico, Albuquerque, New Mexico. Division of Epidemiology, Biostatistics, and Preventive Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Wiggins
authors.affiliation: Cancer Center, University of New Mexico, Albuquerque, New Mexico. Division of Epidemiology, Biostatistics, and Preventive Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.
authors.forename: Huining
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico. Cancer Center, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Lesley
authors.initials: L
authors.lastname: Lomo
authors.affiliation: Cancer Center, University of New Mexico, Albuquerque, New Mexico. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of New Mexico School of Medicine, Albuquerque, New Mexico.
authors.forename: Carolyn Y
authors.initials: CY
authors.lastname: Muller
authors.affiliation: Department of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico. Cancer Center, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Angela
authors.initials: A
authors.lastname: Wandinger-Ness
authors.affiliation: Cancer Center, University of New Mexico, Albuquerque, New Mexico. Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, New Mexico.
authors.forename: Laurie G
authors.initials: LG
authors.lastname: Hudson
mesh_terms: D000368:Aged; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020910:Ketorolac / Q000008:administration & dosage*; D020911:Ketorolac Tromethamine / Q000008:administration & dosage; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: C107953:RAC1 protein, human; D020911:Ketorolac Tromethamine; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D017239:Paclitaxel; D020910:Ketorolac