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COX-2 inhibitors. A new class of antiangiogenic agents
J L Masferrer1, A Koki, K Seibert
1Discovery Pharmacology and Analytical Sciences Center, G.D. Searle/Monsanto Company, St. Louis, Missouri 63167, USA. jlmasf@monsanto.com
Abstract:
The formation of new blood vessels by angiogenesis to provide adequate blood supply is a key requirement for the growth of many tumors. While normal blood vessels expressed the COX-1 enzyme, new angiogenic endothelial cells expressed the inducible COX-2. We evaluated the role of COX inhibitors in the mouse corneal micropocket assay in which angiogenesis is driven by the addition of a Hydron pellet containing basic fibroblast growth factor (bFGF). Neovascular areas were measured with a slit lamp five days after pellet implantation into the corneal stroma. All animals containing implants with bFGF (90 ng) developed intensive areas of neovascularization, whereas the controls implanted with the Hydron pellet alone did not. Indomethacin (a nonselective COX-1/COX-2 inhibitor) and SC-236 (a COX-2-selective inhibitor) inhibited angiogenesis in a dose-dependent manner. Importantly, the indomethacin-treated mice developed severe gastrointestinal toxicity at the efficacious dose of 3 mg/kg/day. By contrast, gastrointestinal lesions were not observed, and platelet COX-1 activity was unaffected, at anti-angiogenic doses of SC-236 (1-6 mg/kg/day). Furthermore, a COX-1-selective inhibitor, SC-560, was ineffective at doses up to 10 mg/kg, a dose that completely blocked platelet COX-1 activity in these mice. SC-236 was also effective in reducing angiogenesis driven by bFGF, vascular endothelium growth factor (VEGF), or carrageenan in the matrigel rat model. Finally, in several tumor models, SC-236 consistently and effectively inhibited tumor growth and angiogenesis. This novel antiangiogenic activity of COX-2 inhibitors indicates their potential therapeutic utility in several types of cancer.
Insights
Cyclooxygenase-2 (COX-2) inhibitors effectively reduced tumor growth and angiogenesis by blocking new blood vessel formation. Unlike non-selective inhibitors, COX-2 selective inhibitors showed therapeutic potential without causing gastrointestinal toxicity.
Area of Science:
- Oncology
- Pharmacology
- Vascular Biology
Background:
- Tumor growth necessitates angiogenesis, the formation of new blood vessels.
- Cyclooxygenase-2 (COX-2) is upregulated in angiogenic endothelial cells, unlike the constitutively expressed COX-1 in normal vessels.
Purpose of the Study:
- To evaluate the anti-angiogenic and anti-tumor effects of COX inhibitors, particularly selective COX-2 inhibitors.
- To assess the safety profile of COX inhibitors regarding gastrointestinal toxicity and platelet function.
Main Methods:
- Mouse corneal micropocket assay using basic fibroblast growth factor (bFGF) to induce angiogenesis.
- Inhibition of angiogenesis was measured using slit lamp examination.
- Tumor growth and angiogenesis were evaluated in multiple tumor models.
- Assessment of gastrointestinal toxicity and platelet COX-1 activity.
Main Results:
- Both nonselective (Indomethacin) and COX-2 selective (SC-236) inhibitors dose-dependently inhibited angiogenesis.
- Indomethacin caused significant gastrointestinal toxicity, whereas SC-236 did not at effective anti-angiogenic doses.
- COX-1 selective inhibitor (SC-560) was ineffective in inhibiting angiogenesis.
- SC-236 demonstrated efficacy in reducing angiogenesis induced by bFGF, VEGF, or carrageenan in different models.
- SC-236 effectively inhibited tumor growth and angiogenesis in various tumor models.
Conclusions:
- Selective COX-2 inhibition is a promising strategy for anti-angiogenic cancer therapy.
- COX-2 inhibitors offer a potential therapeutic window, avoiding the toxicity associated with nonselective COX inhibitors.
- Targeting COX-2 represents a novel approach for cancer treatment due to its anti-angiogenic and anti-tumor properties.