Simultaneous reduction in cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2

Mary Ann C Sabino, Joseph R. Ghilardi, Joost L M Jongen, Cathy P. Keyser, Nancy M. Luger, David B. Mach, Christopher M. Peters, Scott D. Rogers, Matthew J. Schwei, Carmen De Felipe, Patrick W Mantyh

Research output: Contribution to journalArticle

172 Citations (Scopus)

Abstract

More than half of all chronic cancer pain arises from metastases to bone, and bone cancer pain is one of the most difficult of all persistent pain states to fully control. Several tumor types including sarcomas and breast, prostate, and lung carcinomas grow in or preferentially metastasize to the skeleton where they proliferate, and induce significant bone remodeling, bone destruction, and cancer pain. Many of these tumors express the isoenzyme cycloxygenase-2 (COX-2), which is involved in the synthesis of prostaglandins. To begin to define the role COX-2 plays in driving bone cancer pain, we used an in vivo model where murine osteolytic 2472 sarcoma cells were injected and confined to the intramedullary space of the femur in male C3HHeJ mice. After tumor implantation, mice develop ongoing and movement-evoked bone cancer pain-related behaviors, extensive tumor-induced bone resorption, infiltration of the marrow space by tumor cells, and stereotypic neurochemical alterations in the spinal cord reflective of a persistent pain state. Thus, after injection of tumor cells, bone destruction is first evident at day 6, and pain-related behaviors are maximal at day 14. A selective COX-2 inhibitor was administered either acutely [NS398; 100 mg/kg, i.p.] on day 14 or chronically in chow {MF. tricyclic; 0.015%, p.o.} from day 6 to day 14 after tumor implantation. Acute administration of a selective COX-2 inhibitor attenuated both ongoing and movement-evoked bone cancer pain, whereas chronic inhibition of COX-2 significantly reduced ongoing and movement-evoked pain behaviors, and reduced tumor burden, osteoclastogenesis, and bone destruction by >50%. The present results suggest that chronic administration of a COX-2 inhibitor blocks prostaglandin synthesis at multiple sites, and may have significant clinical utility in the management of bone cancer and bone cancer pain.

Original languageEnglish (US)
Pages (from-to)7343-7349
Number of pages7
JournalCancer Research
Volume62
Issue number24
StatePublished - Dec 15 2002
Externally publishedYes

Fingerprint

Bone Neoplasms
Cyclooxygenase 2
Growth
Neoplasms
Bone and Bones
Pain
Sarcoma
Prostaglandin Antagonists
Inhibition (Psychology)
Cancer Pain
Bone Remodeling
Bone Resorption
Tumor Burden
Osteogenesis
Skeleton
Chronic Pain
Femur
Isoenzymes
Prostaglandins
Prostate

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sabino, M. A. C., Ghilardi, J. R., Jongen, J. L. M., Keyser, C. P., Luger, N. M., Mach, D. B., ... Mantyh, P. W. (2002). Simultaneous reduction in cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2. Cancer Research, 62(24), 7343-7349.

Simultaneous reduction in cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2. / Sabino, Mary Ann C; Ghilardi, Joseph R.; Jongen, Joost L M; Keyser, Cathy P.; Luger, Nancy M.; Mach, David B.; Peters, Christopher M.; Rogers, Scott D.; Schwei, Matthew J.; De Felipe, Carmen; Mantyh, Patrick W.

In: Cancer Research, Vol. 62, No. 24, 15.12.2002, p. 7343-7349.

Research output: Contribution to journalArticle

Sabino, MAC, Ghilardi, JR, Jongen, JLM, Keyser, CP, Luger, NM, Mach, DB, Peters, CM, Rogers, SD, Schwei, MJ, De Felipe, C & Mantyh, PW 2002, 'Simultaneous reduction in cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2', Cancer Research, vol. 62, no. 24, pp. 7343-7349.
Sabino MAC, Ghilardi JR, Jongen JLM, Keyser CP, Luger NM, Mach DB et al. Simultaneous reduction in cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2. Cancer Research. 2002 Dec 15;62(24):7343-7349.
Sabino, Mary Ann C ; Ghilardi, Joseph R. ; Jongen, Joost L M ; Keyser, Cathy P. ; Luger, Nancy M. ; Mach, David B. ; Peters, Christopher M. ; Rogers, Scott D. ; Schwei, Matthew J. ; De Felipe, Carmen ; Mantyh, Patrick W. / Simultaneous reduction in cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2. In: Cancer Research. 2002 ; Vol. 62, No. 24. pp. 7343-7349.
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abstract = "More than half of all chronic cancer pain arises from metastases to bone, and bone cancer pain is one of the most difficult of all persistent pain states to fully control. Several tumor types including sarcomas and breast, prostate, and lung carcinomas grow in or preferentially metastasize to the skeleton where they proliferate, and induce significant bone remodeling, bone destruction, and cancer pain. Many of these tumors express the isoenzyme cycloxygenase-2 (COX-2), which is involved in the synthesis of prostaglandins. To begin to define the role COX-2 plays in driving bone cancer pain, we used an in vivo model where murine osteolytic 2472 sarcoma cells were injected and confined to the intramedullary space of the femur in male C3HHeJ mice. After tumor implantation, mice develop ongoing and movement-evoked bone cancer pain-related behaviors, extensive tumor-induced bone resorption, infiltration of the marrow space by tumor cells, and stereotypic neurochemical alterations in the spinal cord reflective of a persistent pain state. Thus, after injection of tumor cells, bone destruction is first evident at day 6, and pain-related behaviors are maximal at day 14. A selective COX-2 inhibitor was administered either acutely [NS398; 100 mg/kg, i.p.] on day 14 or chronically in chow {MF. tricyclic; 0.015{\%}, p.o.} from day 6 to day 14 after tumor implantation. Acute administration of a selective COX-2 inhibitor attenuated both ongoing and movement-evoked bone cancer pain, whereas chronic inhibition of COX-2 significantly reduced ongoing and movement-evoked pain behaviors, and reduced tumor burden, osteoclastogenesis, and bone destruction by >50{\%}. The present results suggest that chronic administration of a COX-2 inhibitor blocks prostaglandin synthesis at multiple sites, and may have significant clinical utility in the management of bone cancer and bone cancer pain.",
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