Opioid Analgesics Promote Tumor Growth by Stimulating NOS/COX-2 Signaling: Prevention by COX-2 Inhibitors Jesus A. Cabrera, *Robert J. Griffin, Rong Luo, *Brent W. Williams, Aaron Udager, Surajit Dhara,*Chang W. Song, Robert P. Hebbel & Kalpna Gupta. Division of Hematology, Oncology & Transplantation & *Therapeutic Radiology, University of Minnesota, Minneapolis, MN 55455. Opioids are a cornerstone therapy for treatment of cancer pain. We showed that morphine promotes breast tumor growth in mice by stimulating tumor angiogenesis (Gupta, K. et al, Cancer Research 2002). We demonstrate that hydromorphone, fentanyl, and oxycodone in clinically relevant doses promote tumor growth and tumor neovascularization to the same extent as morphine. In addition we observed that morphine promotes tumor growth in 4 different tumor models: 1) human MDA MB 231 BO cells xenografted in nude mice, 2) SCK cells in A/J mice, 3) NCTC 2472 cells in C3H/HeJ mice, and 4) T-241 fibrosarcoma cells in C57/BL6 mice. In MDA MB 231 BO model, morphine (equivalent of 200mg/70 Kg human/day) caused 13% increase in tumor volume by the 15th day and a 37% increase on the 22nd day as compared to controls (P, 0.05 and <0.05, respectively). In the faster growing SCK syngeneic mouse tumor model, morphine (equivalent of 500 mg/70 Kg human/day) promoted tumor growth by 28% by day 13 and by 57% on day 14 (P, 0.05 and <0.05, respectively, vs control). In the other two models morphine induced tumor growth to the a similar extent. This was accompanied by significantly increased tumor microvessel density, vessel numbers, total vessel length and vessel branching in morphine treated mice (P <0.05 vs Control). Increased tumor growth and angiogenesis coincided with increased metastasis in morphine-treated mice. We observed 50% higher lung metastasis on day 12 and 20% more advanced metastasis on day 15, in morphine treated mice vs controls. Mechanistically, opioid analgesics stimulated pro-angiogenic signaling by activating time-dependent MAPK/ERK phosphorylation in vitro in human microvascular endothelial cells. We observed upregulated expression of inducible and endothelial nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2) in opioid treated mice vs controls on Western immunobloting. Immunohistochemically, increased eNOS expression co-localized to the tumor endothelium, whereas, increased iNOS and COX-2 expression co-localized to tumor cells. Inhibition of nitric oxide synthase by L-NAME (25 mg/Kg) or COX-2 by Celecoxib (30 mg/Kg), prevented morphine enhanced tumor growth in SCK tumor model. Morphine or Celecoxib given alone impaired the quality of life (measured as decreased body weight, poor locomotion and impaired ability to reach food and water) and decreased survival. Mice receiving Celecoxib alone started losing weight after 4 days and started dying after 5 days of treatment. Similarly, morphine treatment alone reduced their survival by 30%. Importantly, Celecoxib, when given in combination with morphine appreciably increased survival and improved quality of life. These data show that a combination of morphine and Celecoxib provide an advantage to tumor bearing mice by preventing tumor growth (and possibly metastasis) which leads to improved quality of life and survival. It suggests a definite advantage of using combination therapy of opioid analgesic plus COX-2 inhibitor(s) to clinically manage pain in cancer patients without influencing tumor progression or compromising their quality of life and survival. AACR Abstract Number: LB-149, 2003 Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.