Cancer Letters

Cancer Letters

Volume 147, Issues 1–2, 1 December 1999, Pages 187-193
Cancer Letters

Termination of piroxicam treatment and the occurrence of azoxymethane-induced colon cancer in rats

https://doi.org/10.1016/S0304-3835(99)00296-7Get rights and content

Abstract

Piroxicam has been shown to prevent azoxymethane (AOM)-induced colon cancer when administered during the promotion/progression phase. The requirement for continued treatment with piroxicam in order to maintain prevention of colon cancer was investigated. Male F344 rats were administered 15 mg/kg AOM at 7 and 8 weeks of age and started to receive piroxicam (200 mg/kg) in their diet at 11 weeks after the second dose of AOM. Piroxicam was removed from the diet of some of the rats at weeks 19 and 28 and the animals were held until week 47. Other rats continued to receive piroxicam until sacrificed at week 47. Treatment with piroxicam from week 11–47 reduced the yield of colon tumors. When treatment was terminated at week 19 or 28 the yield of tumors at week 47 was not reduced. Within 1 week of the start of piroxicam treatment, the number of aberrant crypt foci (ACF)/animal was decreased. Termination of treatment resulted in the recurrence of ACF. Apoptosis in adenomas was increased when piroxicam treatment was continued to week 47 but not when treatment was terminated earlier at week 19 or 28. The proliferating cell nuclear antigen-labeling index in adenomas was not affected by piroxicam even when treatment was from week 11 to 47. In summary, termination of treatment resulted in the occurrence of ACF and colon cancer indicating that prevention by piroxicam was reversible. Furthermore, enhancement of apoptosis and not decreased cell proliferation correlated with prevention of colon cancer.

Introduction

Piroxicam is a non-steroidal anti-inflammatory drug (NSAID) used for the treatment of inflammatory arthritis. NSAIDs inhibit cyclooxygenases (COX-1 and COX-2) which results in decreased synthesis of prostaglandins including E2 and F2α [1], [2], [3]. Increased levels of prostaglandins have been associated with carcinogenesis in the colon, so that reduction of their level by NSAIDs would suggest prevention of cancer. NSAIDs including aspirin, piroxicam and sulindac have demonstrated efficacy in preventing azoxymethane (AOM)-induced colon cancer in rats [4], [5], [6], [7], [8], [9], [10]. Piroxicam and sulindac were very effective in preventing colon cancer when administered after AOM indicating that they are active during the promotion/progression phase of carcinogenesis [4], [7]. Furthermore, a variety of epidemiological and clinical studies have supported the prevention of colon cancer by NSAIDs [11], [12], [13], [14], [15], [16], [17], [18], [19]. Hence, NSAIDs appear to be promising chemopreventive agents for colon cancer.

The development of adenomatous polyps and invasive cancer are primary endpoints in colon neoplasia. However, an earlier lesion, aberrant crypt focus (ACF) is observed in the colon of carcinogen treated mice and rats [20], [21], [22] and in human colon [23], [24]. ACF are readily identified in whole mounts of colon as containing crypts with elongated openings and thicker epithelial lining than normal crypts [20]. ACF also exhibit characteristics in common with colon tumors including hyperplasia, dysplasia and activated K-ras oncogene [21]. Thus, the ability to prevent ACF has been used as a screen for chemopreventive agents. NSAIDs including aspirin, ibuprofen, indomethacin, ketoprofen, piroxicam and sulindac have been shown to prevent AOM-induced ACF [25], [26]. Piroxicam also caused the regression of ACF [10], [27].

In humans the decreased risk of colorectal cancer associated with the use of NSAIDs appears to require sustained use of the drug [12], [14], [19]. Cessation of treatment of FAP patients with sulindac resulted in recurrence and renewed growth of polyps [11], [28]. Similarly, in a case control study, Rosenberg et al. [14] found that when people stopped taking aspirin for at least a year there was no longer an associated decrease in the risk of colorectal cancer. Thus, termination of treatment with an NSIAD appears to annul its preventive activity resulting in the occurrence of colon cancer. This would indicate the need for continued treatment with an NSAID in order to maintain the reduced risk of cancer.

In this study, we determined the effect of termination of treatment with piroxicam on the yield of ACF and colon tumors. Hence, the requirement for continued treatment with piroxicam in order to maintain the prevention of ACF and colon tumors was investigated. Two biomarkers that have been proposed for chemopreventive agents including NSAIDs in the colon are enhancement of apoptosis and decreased cell proliferation [29], [30], [31], [32], [33], [34]. The effect of piroxicam on apoptosis and cell proliferation in adenomas was determined as an indication of the mechanism of piroxicam.

Section snippets

Materials and methods

AOM and piroxicam were purchased from Sigma Chemical Co. (St. Louis, MO). Powdered AIN-76A diet consisting of 20% casein, 52% cornstarch, 13% dextrose, 5% corn oil, 5% alphacel fiber, 3.5% AIN mineral mixture, 1.0% AIN vitamin mixture, 0.3% DL-methionine and 0.2% choline bitartrate was obtained from Dyets Inc. (Bethlehem, PA) and piroxicam was added at our facility.

Male F344 rats were obtained at 6 weeks of age from the National Cancer Institute (Frederick, MD). They were housed and maintained

Results

Body weight was monitored once a week for the first 4 weeks of piroxicam treatment and monthly thereafter without any significant difference among the four treatment groups. Prior to their scheduled sacrifice, 4/73, 4/30, 4/28, and 2/53 rats in Treatment Groups 1, 2, 3 and 4, respectively, were either sacrificed because they were moribund or were found dead.

Discussion

Previous studies with piroxicam [4], [10], sulindac [7] and aspirin [37] have found that the chemopreventive efficacy of these NSAIDs was similar whether treatment was started before or up to 12 weeks post-AOM treatment. We have previously reported that beginning treatment with curcumin, another chemopreventive agent in the colon, or piroxicam at 5 and 11 weeks after AOM, respectively, can induce the regression of ACF [10], [27]. We now report that ACF recurred when treatment with piroxicam was

Acknowledgements

This work was supported in part by the National Cancer Institute, Contract NO1-CN-55151.

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