Effect of matrix metalloproteinase inhibition on pancreatic cancer invasion and metastasis: An additive strategy for cancer control

Ramon E. Jimenez, Werner Hartwig, Bozena A. Antoniu, Carolyn C. Compton, Andrew L. Warshaw, Carlos Fernández-Del Castillo

Research output: Contribution to journalArticle

Abstract

Objective: To investigate the effect of a matrix metalloproteinase (MMP) inhibitor, BB-94, on the viability, invasion, and metastases of pancreatic cancer. Summary Background Data: Inhibitors of MMPs, enzymes that degrade extracellular matrix, have been tested as single chemotherapeutic agents for pancreatic cancer. Methods: Capan1 and AsPC1 cell lines were studied. BB-94 cytotoxicity was evaluated by cell proliferation assays. Production of MMP2 and MMP9 in conditioned media was demonstrated by gelatin zymography. The in vitro effect of BB-94 on cell invasion was assayed using invasion chambers. Hepatic metastases from pancreatic cancer were induced by intrasplenic injections of Capan1 or AsPC1 cells in nude mice. The in vivo effect of BB-94 on liver metastases was evaluated by comparing animals receiving BB-94 treatment with controls receiving vehicle alone. Variables measured included death rate and tumor burden (liver-to-body weight ratio). Results: BB-94 was not cytotoxic between 3 and 3,000 ng/mL. Zymography demonstrated production of MMP2 and MMP9 by both cell lines, with complete inhibition of these enzymes by BB-g4 at 48 ng/mL. Invasion chamber assays showed that BB-g4 (48- 400 ng/mL) impeded cell invasion in vitro compared with untreated controls. In vivo, BB-94 prevented death or reduced the death rate from hepatic metastases in animals injected with Capan1 or AsPC1 cells. BB-94 treatment resulted in significant reductions in hepatic tumor burden compared with untreated controls. Conclusions: Inhibition of MMP reduces both growth of pancreatic cancer metastases and the death rate. These actions do not reflect cytotoxicity but rather result from impaired cancer cell attachment, migration, and organ invasion. MMP inhibitors may provide an additive effect to cytotoxic agents in multidimensional treatment regimens for pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)644-654
Number of pages11
JournalAnnals of Surgery
Volume231
Issue number5
DOIs
StatePublished - May 2000
Externally publishedYes

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Matrix Metalloproteinases
Pancreatic Neoplasms
Neoplasm Metastasis
Matrix Metalloproteinase Inhibitors
Neoplasms
Liver
Tumor Burden
Mortality
Cell Line
batimastat
Cytotoxins
Enzyme Inhibitors
Gelatin
Conditioned Culture Medium
Nude Mice
Cell Movement
Extracellular Matrix
Therapeutics
Body Weight
Cell Proliferation

ASJC Scopus subject areas

  • Surgery

Cite this

Jimenez, R. E., Hartwig, W., Antoniu, B. A., Compton, C. C., Warshaw, A. L., & Fernández-Del Castillo, C. (2000). Effect of matrix metalloproteinase inhibition on pancreatic cancer invasion and metastasis: An additive strategy for cancer control. Annals of Surgery, 231(5), 644-654. https://doi.org/10.1097/00000658-200005000-00004

Effect of matrix metalloproteinase inhibition on pancreatic cancer invasion and metastasis : An additive strategy for cancer control. / Jimenez, Ramon E.; Hartwig, Werner; Antoniu, Bozena A.; Compton, Carolyn C.; Warshaw, Andrew L.; Fernández-Del Castillo, Carlos.

In: Annals of Surgery, Vol. 231, No. 5, 05.2000, p. 644-654.

Research output: Contribution to journalArticle

Jimenez, RE, Hartwig, W, Antoniu, BA, Compton, CC, Warshaw, AL & Fernández-Del Castillo, C 2000, 'Effect of matrix metalloproteinase inhibition on pancreatic cancer invasion and metastasis: An additive strategy for cancer control', Annals of Surgery, vol. 231, no. 5, pp. 644-654. https://doi.org/10.1097/00000658-200005000-00004
Jimenez, Ramon E. ; Hartwig, Werner ; Antoniu, Bozena A. ; Compton, Carolyn C. ; Warshaw, Andrew L. ; Fernández-Del Castillo, Carlos. / Effect of matrix metalloproteinase inhibition on pancreatic cancer invasion and metastasis : An additive strategy for cancer control. In: Annals of Surgery. 2000 ; Vol. 231, No. 5. pp. 644-654.
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