Colon cancer prevention with NO-releasing NSAIDs

Abstract

A seminal advance in the prevention of colon cancer has been the observation that nonsteroidal antiinflammatory drugs (NSAIDs) reduce the incidence of and mortality from colon cancer by about half. Among current efforts to overcome the side effects of NSAIDs, an important limitation for their application as chemopreventive agents, is the synthesis of nitric oxide-releasing NSAIDs. These novel compounds may display greater safety and greater efficacy compared to their parent traditional NSAIDs and thus hold significant promise as chemopreventive agents against human colon cancer. In this review we discuss salient features of their pharmacology, in vitro and animal data pertaining to colon cancer, their mechanisms of action, and assess their potential in the chemoprevention of colon cancer.

Introduction

Colon cancer is the second leading cause of cancer-related deaths in the United States with an estimated 135,000 new cases in 2001 [1]. The limited success of current treatment for advanced colon cancer has provided the impetus for increasing emphasis on cancer prevention. Chemoprevention refers to the administration of chemical or natural agents that may block tumor initiation and promotion [2]. It aims to decrease morbidity and mortality from colon cancer by lowering the risk of developing invasive or clinically significant disease. Colon cancer is well suited for chemoprevention because it is common; is associated with high mortality; has a long incubation period; and its molecular pathogenesis is well understood.

Non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of and mortality from colon cancer by about half and constitute the prototypical colon cancer chemopreventive agents [3]. The use of NSAIDs is limited by their significant toxicity, which includes (a) gastrointestinal side effects, which range from dyspepsia to gastrointestinal bleeding, obstruction, and perforation; (b) renal side effects, and (c) a large number of additional side effects, some of which are serious, ranging from hypersensitivity reactions to the distinct salicylate intoxication. Among patients using NSAIDs, up to 4% per year suffer serious gastrointestinal complications [4]. In 1997, there were 16,500 NSAID-related deaths in the US, virtually the same as from AIDS (16,685) [5].

The clinical usefulness of NSAIDs combined with their potentially life-threatening toxicity has prompted intensive efforts to identify safer alternatives, which will at least maintain their pharmacological properties. Currently, there are at least five classes of medications, which promise to be safer than their traditional NSAID counterparts. They include i) selective COX-2 inhibitors, ii) R-enantiomers of chiral NSAIDs, iii) NSAIDs bound to zwitterionic phospholipids, iv) NSAIDs co-administered with trefoil peptides, and v) nitric oxide-releasing NSAIDs (NO-NSAIDs).

COX-2 inhibitors are as effective as traditional NSAIDs for the indications for which they have been approved and appear to have superior safety [6], [7], [8], accounting in part for their extensive clinical use. Selective COX-2 inhibitors have been very effective in the chemoprevention of colon cancer in animal models [9]. Early treatment (before adenomas developed) with celecoxib, a selective COX-2 inhibitor, decreased tumor multiplicity to 29% and tumor size to 17% of controls, but treatment after adenomas were established reduced these parameters by about half. Their effectiveness in human colon neoplasia may be even less pronounced, although the data to date are limited. In patients with familial adenomatous polyposis, large doses of celecoxib reduced both the number of colorectal polyps and polyp burden by almost one-third [10].

Enantiomers of NSAIDs, NSAIDs bound to zwitterionic phospholipids, or NSAIDs co-administered with trefoil peptides, are at early stages of development and data on them are limited. Here, we focus on NO-NSAIDs, which are emerging as a promising group of safer and perhaps more effective alternatives to traditional NSAIDs. We summarize our current knowledge of NO-NSAIDs, providing the rationale for their synthesis and an overview of their pharmacological properties, followed by a discussion of their potential application to colon cancer prevention.