Elsevier

The Lancet Oncology

Volume 4, Issue 10, October 2003, Pages 605-615
The Lancet Oncology

Review
Inhibitors of cyclo-oxygenase 2: a new class of anticancer agents?

https://doi.org/10.1016/S1470-2045(03)01220-8Get rights and content

Section snippets

Mechanisms of COX2 regulation

Overexpression of COX2 in human cancers is likely to occur via several pathways (figure 2).15 Associations of COX2 with mutated RAS and c-MYB have been found.16, 17 In human colon and liver carcinogenesis, COX2 is transcriptionally downregulated by APC and upregulated by nuclear accumulation of β-catenin, through the Wnt-signalling pathway, whereas K-RAS induces stabilisation of COX2 mRNA.4 However, whether the mechanisms of modulation of COX2 expression are the same in different cell lines is

Antitumoral activity of coxibs

Several prostaglandins, such as PGE2, suppress immunosurveillance through downregulation of lymphokines, T-cell and B-cell proliferation, cytotoxic activity of natural killer cells, and secretion of TNFα and interleukin 10.24 Pai and colleagues25 showed a close link between PGE2 and EGF-receptor signalling systems. PGE2 induces the activation of metalloproteinases MMP2 and MMP9, increases expression of TGFα, transactivates EGF receptor, and triggers mitogenic signalling in gastric epithelial

COX2 expression in human cancers

The evidence on the location of COX2 in solid tumours is conflicting. COX2 is expressed in some colon-carcinoma cell lines53 and is induced in cultured rat intestinal epithelial cells by mitogens.54 Some of the conflict in the findings may be due to the non-specific binding of the polyclonal antibodies used for COX2 immunostaining or to changes in COX2 expression patterns as adenomas progress to carcinomas. In human colorectal cancer, COX2 overexpression is present in both tumour and stromal

Coxibs: pharmacology, drug interactions, and safety profile

Three classes of COX inhibitors have been developed: aspirin; indomethacin and other NSAIDs; and coxibs (celecoxib, rofecoxib, valdecoxib, etoricoxib, and COX-189 or luminaroxib).58 Selectivity for COX2 can be assessed by whole-blood assays in vitro or in vivo, based on the production of thromboxane B2 during blood clotting (an index of platelet COX1 activity) and the production of PGE2 by bacterial lipopolysaccharide in whole blood (an index of monocyte COX2 activity). Genetic variability in

Coxibs in combination anticancer therapy: rationale and preclinical studies

Tumorigenesis is the result of accumulated genetic and epigenetic changes leading to many functional pathways allowed by the inherent genetic instability of cancer cells. Neoplasia is a product of the altered communication between tumour and host microenvironment: The interactions of cancer cells with the microenvironment create a context that promotes tumour growth and protects the tumour from immunosurveillance.64 Therefore, control of tumour growth necessitates combined therapy able to block

Clinical studies with coxibs in advanced tumours

The major areas of research for clinical development of coxibs in oncology are summarised in panel 1. At least 25 clinical studies to assess the efficacy of coxibs alone or in combination with other anticancer agents in patients with advanced tumours are under way (table 2). Most are phase I/II studies aimed at assessing the feasibility of combinations of coxibs with conventional chemotherapy.

Conclusions

There is compelling experimental evidence that inhibition of COX2 causes tumour regression. Pharmacodynamic studies have shown several mechanisms for the anticancer effects of coxibs: blocking of angiogenesis, promotion of apoptosis, modulation of inflammation and immunoresponse, and others. However, we do not yet know which of these is the major pathway of control of tumour growth. Another unresolved issue concerns systematic comparative studies with the available coxibs to establish which is

Search strategy and selection criteria

Published and unpublished data for this review were identified by searches of MEDLINE, EMBASE, and references from relevant articles up to May, 2003. Search terms included “cyclooxygenase”, “COX-2”, “COX-3”, and “nonsteroldal anti-inflammatory drug” which were combined separately with “apoptosis”, “angiogenesis”, “anticancer therapy”, “chemotherapy”, and “tumour”. We consulted drug companies including Pfizer and Marck Sharp & Dohme Pharmaceuticals. Only papers published in English were

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