title: Chronotherapy and chronotoxicity of the cyclooxygenase-2 inhibitor, celecoxib, in athymic mice bearing human breast cancer xenografts.
abstract: OBJECTIVE
  Inhibition of the enzyme cyclooxygenase with celecoxib is cytotoxic in a variety of solid tumor cell lines. Previous work has shown that by charting circadian rhythms, it has been possible to find optimal times to deliver a dose of drug, such that it is most efficacious in killing cancer cells and least harmful to normal tissues. Therefore, we examined the time dependence of toxicity (chronotoxicity) and of antitumor effects (chronotherapy) of celecoxib to determine optimal time of day for dosing with respect to light-dark cycles.
  
  
  METHODS
  Celecoxib was administered i.p. for 10 days (5 days on, 2 days off, 5 days on) to nude mice bearing s.c. breast xenografts. Body weight, peripheral blood cells, clinical chemistry, and tumor growth were monitored.
  
  
  RESULTS
  The highest tolerance (100% survival) was found at 7 HALO and the least occurred at 17 h after light onset (HALO; 10% survival). Chronotherapy at a 20-mg/kg dose varied between the seven HALO evaluated and between the three breast tumors (MCF-7, ZR-75-30, and MDA-MB-468) studied. When the maximum tolerated dose (MTD) of celecoxib was optimized for each HALO, we found that at 7-10 HALO, the MTD was 25 mg/kg, whereas at 17-20 HALO; the MTD was only 10 mg/kg. Tumor regression was observed when dosing was done at 23 HALO to 7 HALO (5 a.m. to 1 p.m.), whereas no therapeutic response was observed when dosing was done at 10-13 HALO (4 p.m. to 7 p.m.), and rapid tumor growth was noted when dosing was done at 17 HALO (11 p.m.).
  
  
  CONCLUSIONS
  Tumor growth response to the MTD at each HALO revealed that there was no clear relationship between dose administered and therapeutic response. COX-2 expression was not able to explain either the chronotherapy or the chronotoxicity results obtained.
authors.affiliation: Garden State Cancer Center, Belleville, New Jersey 07109, USA. rblumenthal.gscancer@att.net
authors.forename: R D
authors.initials: RD
authors.lastname: Blumenthal
authors.forename: C
authors.initials: C
authors.lastname: Waskewich
authors.forename: D M
authors.initials: DM
authors.lastname: Goldenberg
authors.forename: W
authors.initials: W
authors.lastname: Lew
authors.forename: C
authors.initials: C
authors.lastname: Flefleh
authors.forename: J
authors.initials: J
authors.lastname: Burton
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001219:Aspartate Aminotransferases / Q000097:blood / Q000187:drug effects; D001663:Bilirubin / Q000097:blood; D001806:Blood Urea Nitrogen; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology / Q000517:prevention & control; D000068579:Celecoxib; D019454:Chronotherapy; D051546:Cyclooxygenase 2; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome; D014527:Uric Acid / Q000097:blood; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; D012334:RNA, Neoplasm; D013449:Sulfonamides; D014527:Uric Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D001219:Aspartate Aminotransferases; D000068579:Celecoxib; D001663:Bilirubin