Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit colorectal carcinogenesis and prevent or revert the growth of premalignant colonic polyps. They inhibit cyclooxygenase (COX) but recent data indicate that this is not the only or even the most important mechanism of inhibition in colorectal tumor cells. We have used colonic carcinoma and adenoma cell lines to study the effects of the NSAID sulindac sulfide, its COX-inactive metabolite, sulindac sulfone, and the isoenzyme-specific inhibitors SC58125, SC236 and SC58560 on tumor cell growth in relation to COX-2 expression and prostaglandin production. To establish the role of COX-2 in NSAID action, we constructed clones expressing different levels of COX-2 from SW480 cells. All five compounds inhibited DNA synthesis and/or induced apoptosis, each with a characteristic pattern. ID(50)s were very similar in all the cell lines and were independent of COX expression, except for the COX-1 inhibitor SC58560, which was least effective in HT29/HI1, the cell line expressing the highest level of COX-1 (ID(50) 70 microM; in other cells lines the ID(50) was 15 microM). For all other compounds ID(50) concentrations varied less than two-fold: 25-40, 40-90 and 150 microM for SC236, sulindac sulfide and sulindac sulfone, respectively. SC58125 was the weakest inhibitor, never causing >50% cell loss. All compounds modulated expression of Bcl-2 and Bak and activated caspase 3. Overexpression of COX-2 in SW480 cells protected them against induction of apoptosis by sulindac sulfide. The effect was restricted to clones producing high levels of prostaglandin E(2). In summary, our data indicate that both COX-dependent and COX-independent mechanisms are involved in NSAID-induced growth in colorectal tumor cells. The concentrations necessary to inhibit growth were higher than serum concentrations that can be obtained in vivo, indicating that the therapeutic effect of NSAIDs cannot be explained by a direct effect of NSAIDs on the epithelial cells alone. For therapeutic purposes, compounds using different targets could be used to minimize side effects while optimizing therapeutic effect.

Summary:The clinical features and course of 30 patients (26 men and 4 women) under 30 years of age (mean age 27.3 years) with an acute myocardial infarction (MI) are described. The most common risk factor among this group of patients was smoking in 20 patients (66%). The prevalence of the other risk factors was low: hyperlipidemia in four patients and family history of ischemic disease in another four patients, diabetes mellitus, hypertension, and obesity each in one patient. Seven patients (23%) had none of the conventional risk factors. Three patients were exerting themselves prior to the onset of their MI pain; all of them had normal coronaries. Five patients experienced chest pain prior to MI, among them only two experienced classical angina pectoris. Eighteen patients underwent uncomplicated MI. The complications in the other 12 during the acute MI were rhythm disturbances in eight and congestive heart failure in four. Cardiac catheterization was performed in 25 patients. The Occurrence of zero, one, or multivessel disease was equal. The 30 patients were followed up from six months to 15 years (mean 7 years). In 18 patients circulating aggregated platelets were measured one year after the MI. Elevated values were found in all of them (mean+-SD 34.9? 9.1%). In 6 of the 18, all heavy smokers, extreme values were found in the range of 39-55%. Three out of the 30 patients died within five years after their first MI. The other 15 patients developed complications, most of them angina pectoris. Five patients were hospitalized for reinfarction. None of the 30 underwent aortocoronary bypass operation. According to our study the following conclusions could be drawn in MI patients under 30: (1) The main risk factor in this group of patients was smoking, the prevalence of the other conventional coronary risks factors being low. (2) Exertion and chest pain are not prerequisite conditions preceding MI in these patients. (3) The probability of finding zero, one, or multivessel disease on coronary angiography in this group of young MI patients is equal. (4) In MI patients under 30, increased circulating aggregated platelets may play a pathogenetic role in the development of MI.

No abstract

No abstract