title: Celecoxib and mucosal protection: translation from an animal model to a phase I clinical trial of celecoxib, irinotecan, and 5-fluorouracil.
abstract: OBJECTIVE
  Chemotherapy-induced diarrhea occurs secondary to mucosal inflammation and may be cyclooxygenase-2 mediated. Cyclooxygenase-2 inhibitors may ameliorate chemotherapy-induced mucosal toxicity and enhance its antitumor effect. We investigated this hypothesis in the Ward colorectal cancer rat model and in a phase I clinical study.
  
  
  METHODS
  In the Ward rat model, irinotecan was given daily x 3 or weekly x 4 with or without celecoxib. In the phase I clinical study, we planned to escalate the dose of irinotecan in the FOLFIRI regimen (irinotecan, 5-fluorouracil, and leucovorin) with a fixed dose of celecoxib. Irinotecan was escalated in four dose levels: 180, 200, 220, and 260 mg/m2. Celecoxib was administered as 400 mg, twice daily starting on day 2 of cycle 1. Pharmacokinetics of irinotecan, SN-38, and SN-38G were obtained on days 1 and 14. A standard 3+3 dose escalation scheme was used. Plasma concentrations of irinotecan, SN-38, and SN-38G were measured using high-pressure liquid chromatography.
  
  
  RESULTS
  Celecoxib ameliorated diarrhea, weight loss, and lethality and resulted in synergistic antitumor effect in the rat model. Twelve patients with advanced cancers were enrolled and evaluable for dose-limiting toxicity (DLT). Diarrhea was the cause for discontinuation in one. Grade 2 and 3 diarrhea occurred in three and two patients, respectively. One patient had DLT at dose level 2 (grade 3 diarrhea). Two had a DLT at DL3 (G3 emesis and myocardial infarct). Celecoxib had limited influence on the pharmacokinetics of irinotecan in this data set.
  
  
  CONCLUSIONS
  Maximum tolerated dose of irinotecan in FOLFIRI schedule with celecoxib is 200 mg/m2.
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Institute, Houston, Texas 77030, USA. mjavle@mdanderson.org
authors.forename: Milind M
authors.initials: MM
authors.lastname: Javle
authors.forename: Shousong
authors.initials: S
authors.lastname: Cao
authors.forename: Farukh A
authors.initials: FA
authors.lastname: Durrani
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Pendyala
authors.forename: David D
authors.initials: DD
authors.lastname: Lawrence
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Smith
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Creaven
authors.forename: Diane C
authors.initials: DC
authors.lastname: Noel
authors.forename: Renuka V
authors.initials: RV
authors.lastname: Iyer
authors.forename: Youcef M
authors.initials: YM
authors.lastname: Rustum
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068579:Celecoxib; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000627:therapeutic use; D005965:Glucuronates / Q000008:administration & dosage; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000473:pathology; D000077146:Irinotecan; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D020714:Maximum Tolerated Dose; D052016:Mucositis / Q000139:chemically induced*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D013449:Sulfonamides / Q000008:administration & dosage* / Q000627:therapeutic use*
chemical_list: C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide; D000970:Antineoplastic Agents; D005965:Glucuronates; D011720:Pyrazoles; D013449:Sulfonamides; D000077146:Irinotecan; D000068579:Celecoxib; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin