COX-2 inhibitors limit cachexia as well as tumor progression

Despite the number of available cancer therapeutics, heavy R&D investment has driven over one thousand innovative compounds into clinical development, many of which are now reaching, or are about to reach the market, fuelling further expansion (for an analysis of the mid-term cancer market click here or here).

Several lines of evidence suggest that the cyclooxygenase enzymes (specifically COX-2) might be an important molecular target for the intervention of cancer at both early and late stages of some cancers, providing an opportunity for both cancer prevention and therapy (see the Focus on Oncology section of this edition of TherapeuticAdvances for the development of NSAIDs as chemopreventives). COX-2 is overexpressed during carcinogenesis, and appears to have a role in both tumor initiation and promotion and is amenable to intervention. The chemopreventive efficacy of NSAIDs against colorectal cancer has been established. Also, NSAIDs may decrease the incidence of carcinomas of the esophagus, stomach, breast, lung, prostate, urinary bladder and ovary. The COX-2 inhibitor celebrex has been evaluated in patients with familial adenomatous polyposis, a genetic condition that often leads to colorectal cancer. The number of colorectal polyps in these patients was reduced by 28% leading to celebrex being approved by the FDA in 1999 for the treatment of this condition.

Although most cancer research is directed towards the prevention of tumor progression, growing interest in cachexia has been observed over recent years. Cachexia, characterized by a selective loss of lean body mass, is a critical problem in cancer patients (as well as patients with other chronic disease), with up to 20% of cancer deaths directly attributable to this syndrome. Patients with even a modest weight loss at time of cancer diagnosis show a poorer prognosis and a reduced response to chemotherapy. Cachexia differs from anorexia or starvation in that weight is lost from skeletal muscle and fat stores equally. Furthermore, although anorexia and starvation can be attributed to reduced food intake, weight loss from cachexia cannot. Loss of muscle mass leads to a reduction in quality of life and general well being.

Numerous circulating factors have been implicated in cachexia, including increased levels of cytokines and eicosanoids. Prostaglandin release appears to contribute to pathological muscle catabolism both directly and through the regulation of proinflammatory cytokine expression. NSAIDs have been shown to block the protein catabolic effects of serum from cachectic mice and have been reported to prevent muscle protein breakdown in some tumor-bearing rats possibly as a result of reduced energy expenditure. In a recent clinical study the addition of ibuprofen to the treatment protocol of gastrointestinal cancer patients reversed a weight loss of 2.8 kg over 12 weeks to a weight gain of 2.3 kg along with an improvement in quality of life. Given this body of data it is possible that COX-2 inhibitors may not only prevent and limit the development of tumors but that they may also control of some aspects of cachexia.

In numerous models, tumor-bearing animals treated with COX-2 inhibitors retained body weight and overall health compared with vehicle-treated animals. In a recent study Davis et al from PTC Therapeutics report that celecoxib delayed tumor growth however even when the tumors in these mice had reached a size at which massive weight loss was observed in controls, there was little observable cachexia. The authors suggested that prostaglandin production as a result of COX-2 activity within the tumor environment contributed to cachexia. COX-1 activity did not contribute to the development of cachexia.

The global market for COX-2 inhibitors surpassed $6 billion in sales in 2002 (click here for an analysis of the COX market). The ability of COX-2 inhibitors to prevent or limit the growth of certain tumors is likely to expand this market. The beneficial anti-cachexic effects of celecoxib described in the present study suggest that COX-2 inhibition may be beneficial even late on in the progression of cancer expanding the market still further. Human studies designed to extend these findings into the clinical setting are eagerly awaited.

Entry date Wednesday, April 14, 2004

Adapted from Davis et al, J Pharmacol Exp Ther. 2004 Mar;308(3):929-34