Cancer Letters

Cancer Letters

Volume 202, Issue 2, 30 December 2003, Pages 131-136
Cancer Letters

Chemoprevention of mammary carcinogenesis in female rats by rofecoxib

https://doi.org/10.1016/j.canlet.2003.08.006Get rights and content

Abstract

Epidemiological and experimental studies indicate that non-steroidal anti-inflammatory drugs play role in the prevention of human neoplasia including mammary gland cancer. In this study, tumour suppressive effects of a selective inhibitor of cyclooxygenase-2 (COX-2) rofecoxib in the prevention of N-methyl-N-nitrosourea (NMU)-induced mammary carcinogenesis in female Sprague–Dawley rats were evaluated. Rofecoxib was dietary administered in two concentrations—0.01 mg/1 g (ROFE 0.001%), or 0.05 mg/1 g (ROFE 0.005%). Rofecoxib decreased the incidence by 40% (ROFE 0.001%) and by 42.5% (ROFE 0.005%) (P=0.043) when compared to the control group. Similarly, tumour frequency and tumour volume decreased depending on an increasing rofecoxib dose by 18.5 or 40% (tumour frequency) and by 35 or 43% (tumour volume). Rofecoxib shifted the rate of fibroadenomas from 15% (control group) to 32% (ROFE 0.001%), or 38% (ROFE 0.005%), respectively. The present study points to pronounced dose-dependent tumour suppressive effects of rofecoxib in mammary carcinogenesis.

Introduction

Mammary gland cancer is the neoplasia with highest incidence in females all over the world. Chemoprevention is assumed to become an effective way to combat the above neoplasia. Non-steroidal anti-inflammatory drugs (NSAIDs) are important drugs suppressing manifestations of inflammation. They are most frequently applied in the treatment of arthritis, pain, and fever. Recently, their preventive effects in cancer disease and myocardial ischemia were discovered. Clinical trials aimed at long-term application of various NSAIDs reported significantly decreased risk of colorectal cancer [26], mammary gland cancer [11], prostatic cancer [19], lung cancer [10] and malignant melanoma [9]. The experimental studies with laboratory animals proved chemopreventive effects of NSAIDs in various types of neoplasia including mammary cancer [8], [20], [25]. Similarly our group proved the chemopreventive effects of indomethacin administered in drinking water [17] and those of nimesulide administered subcutaneously [15] in mammary gland carcinogenesis in female rats.

The effect of NSAIDs is based on suppression of prostanoid synthesis by inhibition of cyclooxygenase (COX) activity. Two isoforms of COX have been identified: constitutive COX-1 isoform and inducible COX-2 isoform found mostly under pathological conditions, e.g. inflammation and neoplasia. Increased activity of COX-2 isoform was found in colorectal, esophagus, stomach and mammary gland carcinomas [6], [16]. COX-2 may influence the process of carcinogenesis through several mechanisms: peroxidase activity of COX-2 supports the conversion of procarcinogens to carcinogens [6], inhibitory effect of prostaglandins in immune reactions was found [23] as well as angiogenetic [28] and antiapoptotic effects [6]. On the other hand, enhanced invasion of tumour cells associated with increased expression of COX-2 was observed [27]. Brueggemeier et al. [5] reported the linear dependence between aromatase gene (CYP 19) expression and expression of both COX isoforms. The aforementioned facts predetermine the use of NSAIDs in mammary gland cancer prevention.

From pharmacodynamic point of view inhibitors COX-1 (e.g. aspirin, indomethacin, ibuprofen) have a wide range of side effects on gastrointestinal tract. These undesirable effects are markedly reduced in selective COX-2 inhibitors (e.g. celecoxib, nimesulide, meloxicam) [22]. This fact enables their long-term application. Rofecoxib represents the latest NSAIDs generation that selectively suppresses COX-2 activity in human cells in vitro with minimal COX-1 activity suppression. The antitumour properties of rofecoxib in mammary gland cancer were not tested so far. The aim of this work was to assess the chemopreventive effects of rofecoxib in mammary carcinogenesis in female Sprague–Dawley rats.

Section snippets

Materials and methods

Female rats of Sprague–Dawley strain obtained from AnLab (Prague, Czech Republic) aged 33–35 days were used in the experiment. The animals were adapted to standard vivarium conditions with temperature 23±2 °C, relative humidity 60–70%, artificial regimen light:dark (12:12 h) (lights on from 7 a.m., light intensity 150 lux per cage). During the experiment, animals drank tap water ad libitum. The chow containing rofecoxib (Vioxx) synthesized at Merck Research Laboratories (Merck Frosst, Montreal,

Results

Preventive effects of rofecoxib in female rat mammary carcinogenesis are summarized in Table 1 and continuous development of tumour incidence is presented in Fig. 1. In the control group without rofecoxib, 69.6% of animals developed mammary tumours, the tumour frequency was 1.74±0.32, tumour volume 2.85±1.23 cm3 and tumour latency 80.06±6.03 days. Rofecoxib administered in a lower dose in experimental group ROFE 0.001% decreased the incidence of mammary neoplasia by 40% (P=0.058), their

Discussion

This study is the first report on tumour suppressive effects of rofecoxib—selective COX-2 inhibitor in experimental mammary carcinogenesis. Antitumour effect of rofecoxib was recorded in all evaluated parameters of mammary carcinogenesis. In addition, a clear dose-dependent rofecoxib action was observed. Similarly, dose-dependent chemopreventive effect of dietary administered rofecoxib was recorded by Oshima et al. [21] in colorectal carcinogenesis in recombinant APCΔ716 mice. We observed a

Acknowledgements

We wish to thank Merck Research Laboratories (Merck Frosst, Montreal, Canada) for the generous gift of rofecoxib. We thank L. Sokol, MD, head of the Department of Pathology, Faculty Hospital, Tr. SNP 1, Košice, for histological analysis of mammary tumours. The experiments were conducted according to the principles provided in the Law No. 115/1995 §24 of Slovak Republic for the Care and Use of Laboratory Animals.

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