Colon cancer prevention with NO-releasing NSAIDs
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.
Section snippets
The pharmacology of NO-NSAIDs
The synthesis of NO-NSAIDs represents a novel approach to reduce the side effects of NSAIDs, especially their gastric toxicity. Their development was based on the observation that NO possesses some of the same properties as PGs within the gastric mucosa. Coupling a NO-releasing moiety to an NSAID might deliver NO to the site of NSAID-induced damage, thereby decreasing gastric toxicity.
NO is believed to play an important role in gastric cytoprotection, possibly by increasing mucosal blood flow,
Pharmacological effects of NO-NSAIDs
NO-NSAIDs share many pharmacological properties with their parent NSAIDs. From all available data, it emerges that NO-NSAIDs have two characteristic differences from their parent compounds: in general, a) they are more effective regarding key pharmacological actions, and b) they have diminished toxicity. Since the study of this potentially large class of compounds is in its infancy, it is premature to predict whether this interesting pattern will be manifested in humans and whether it will
NO-NSAIDs and colon cancer prevention
The impressive chemopreventive effect of traditional NSAIDs against colon cancer has been unambiguously documented by nearly twenty studies involving hundreds of thousands of patients. As already stated, this has provided the impetus to develop safer and/or more efficacious compounds, including NO-NSAIDs. To date, findings on the chemopreventive potential of NO-NSAIDs, although limited to preclinical studies, appear quite promising. Both cell culture and animal studies have been reported.
Potential mechanisms of action in chemoprevention
NO-NSAIDs appear to be superior to traditional NSAIDs in colon cancer prevention, but the exact mechanism of their action and enhanced effectiveness is still not completely understood. The spacer part of the molecule and the −NO2 group, which releases NO, must contribute to this effect; our data indicate that most of this effect can be accounted for by the contribution of the −NO2 group [12]. Possible mechanisms include:
I) Effect on cell kinetics and cell cycle: As mentioned above, NO-NSAIDs
A special consideration for NO-NSAID use in colon cancer prevention
NO is being recognized as an important player in carcinogenesis. Since NO-NSAIDs are releasing NO, one should consider whether this might promote colon cancer development. This question can be approached by considering the following three parameters: a) the role of NO in colon carcinogenesis, b) the levels of NO in blood and colon tissues in patients receiving NO-NSAIDs, and c) preclinical results with NO-NSAIDs in colon cancer.
First, NO exerts dichotomous effects on cancer. It is critical for
Conclusions
NO-NSAIDs are a novel class of compounds designed to overcome the serious side effects of traditional NSAIDs. Currently, their evaluation for their many envisioned applications in medicine is mostly at a preclinical stage. Thus, it is premature to conclude or even predict with a high degree of confidence what their final position in human therapeutics will be.
All available evidence, however, suggests that this class of ingenious drugs holds out great promise to become a versatile therapeutic
Acknowledgements
This work was supported by NIH Grant CA92423.
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