Nitric oxide, prostanoids, cyclooxygenase, and angiogenesis in colon and breast cancer.

PURPOSE: Several studies have shown an overexpression of cyclooxygenase-2 (COX-2) and elevated levels of prostacyclin (PGI(2)) and thromboxane (TXA(2)) in colon cancer. In this report, we determined the distribution of inducible form of nitric oxide synthase (iNOS), PGI(2), and TXA(2) in cancerous and adjoining areas of specimens from human colon and breast cancer obtained during surgery. Additionally, we investigated differences in expression and histological localization of COX-2 in colon and breast cancer. EXPERIMENTAL DESIGN: Specimens were obtained during surgery, one centrally located, the second from an adjacent, cancer-free area. Activity of iNOS was determined, using the conversion of L-[(14)C]arginine to L-[(14)C]citrulline. PGI(2) and TXA(2) were measured as their stable metabolites, using enzyme immunoassay. A standard immunoperoxidase method was used for immunohistochemical expression of COX-2. RESULTS: Significant differences in iNOS, PGI(2), and TXA(2) expressions between colon and breast cancer were noted, with an enhanced expression of COX-2 in colon cancer, including the cancerous, adjoining, and stromatous fields. CONCLUSIONS: Increased expression of iNOS and production of prostanoids in colon cancer parallels the increase in COX-2, confirming the importance of this enzyme in colon cancer. The overexpression of COX-2, prostanoids, and nitric oxide in areas adjoining the tumor indicates increased metastatic potential for neoplastic cells in this area. Inflammatory changes in the tissue adjoining the cancer may play a role. COX-2 may result in the formation of new blood vessels and the spread of cancer.

beta-blockers reduce the incidence of cardiac events in post-myocardial infarction patients.

The capacity of beta-blockers to prevent cardiac events in post-myocardial infarction (MI) patients was investigated. Among 1,483 study participants, a beta-blocker was included in the therapeutic regimens of 833 (beta-blocker group) and was omitted from the regimens of 650 (control group). The incidence of cardiac events (recurrent MI, sudden death and death by congestive heart failure) during a follow up period of 17.4 +/- 20.9 months was retrospectively compared between the two groups. Cardiac events occurred in 27 (3.2%) members of the beta-blocker group and in 44 (6.8%) controls, which represents a significant decline in the incidence of cardiac events among patients administered beta-blockers (p < 0.01, odds ratio 0.46, 95 % confidence intervals 0.28-0.75). Subgroup and multivariate analyses showed beta-blockers to be as efficacious in Japanese post-MI patients as was previously shown in Western patients. While these findings are compelling, it is clear that confirmation in a large, multicenter, placebo - controlled, randomized clinical trial, analogous to those that have been carried out in Western countries, is necessary.

Basic fibroblast growth factor caused no change in collateral flow or infarct size of acutely-infarcted myocardium in rats.

The extent to which local administration of basic fibroblast growth factor (bFGF) increased regional myocardial blood flow (Qm) to acutely-infarcted areas of the heart, thereby mediating myocardial salvage, was examined in this study. Myocardial infarction was induced in two groups of rats by ligation of the left coronary artery. The bFGF group (n = 16) received 100 microg bFGF in physiological saline by intramyocardial injection into the infarcted area, while the control group (n = 7) received only saline. The rats were then maintained for four weeks. Among the controls, Qm decreased in the infarcted areas to 6.5+/-6.7% of that in the noninfarcted areas immediately after coronary ligation, then increased to 11.5+/-8.6% during the four-week maintenance period. In the bFGF group, Qm immediately decreased to 17.5+/-14.7% following ligation and remained stable thereafter (18.3+/-9.1%). There were no significant differences between the bFGF and control groups with respect to Qm, the number of viable myocardial cells or the extent of myocardial fibrosis. In this study we failed to show any significant effect of bFGF on coronary angiogenesis in acutely-ischemic myocardium in rats. Application of bFGF using different dosage, different routes of administration, measuring new capillaries morphologically will be needed to confirm the present negative results.

[Drug treatment for secondary prevention of myocardial infarction].

The effects of drug treatment on cardiac events for 11 years from January 1986 to December 1996 were investigated in 1,483 patients with myocardial infarction, 1,164 men and 319 women (mean age 60.1 +/- 11.2 years), followed up for 17.4 +/- 20.9 months. Seventy-one patients (4.8%, 33 cases per 1,000 person-year) had cardiac events (recurrent myocardial infarction, sudden death and death by congestive heart failure). Multivariate analysis showed treatment with cholesterol lowering agents and beta-blockers reduced cardiac events, whereas administration of antiarrhythmic agents increased cardiac events. Univariate analysis showed that the incidence of cardiac events was 2.2% in patients treated with cholesterol lowering agents but 6.2% in patients without treatment, showing a significant difference (p < 0.01). The incidence was 3.2% for patients treated with beta-blockers and 6.8% for those without (p < 0.01), showing that beta-blockers were also effective to reduce cardiac events. Antiplatelet agents were also effective (3.7% vs 7.1%, p < 0.01). Calcium antagonists, angiotensin converting enzyme inhibitors and warfarin were not effective. Nitrates (6.0% vs 3.1%, p < 0.01) and antiarrhythmic agents (13.7% vs 3.6%, p < 0.01) increased the incidence of cardiac events. A placebo-controlled, double blind, large clinical multicenter study is required to confirm these results.

Retrospective analysis showing less cardiac events in post-myocardial infarction patients treated with metoprolol. Secondary Prevention Group.

This analysis was carried out to clarify the capacity of metoprolol to prevent cardiac events in Japanese post-myocardial infarction patients during a follow-up period of 16.3 months. Cardiac events occurred in 44 of 650 patients treated without beta-blockers (6.8%) and in 13 of 432 patients treated with metoprolol (3.0%), which represents a significant decline in the incidence of cardiac events among patients receiving metoprolol (p<0.01, odds ratio 0.43, 95% confidence interval 0.23-0.80). Because this was a retrospective analysis, there were unavoidable differences in the backgrounds of the patients in the 2 groups. Subgroup analyses, each focusing on a specific patient characteristic, were therefore performed. These showed that metoprolol effectively reduced cardiac events in many subgroups. Furthermore, multivariate analysis carried out to exclude any modification based on the differences in patient background confirmed metoprolol to be effective in reducing subsequent cardiac events in post-myocardial infarction patients. A large, randomized, placebo-controlled clinical trial needs to be performed in the Japanese population to confirm the present result.

Intermittent nitrate therapy for prior myocardial infaraction does not induce rebound angina nor reduce cardiac events.

OBJECTIVE: Long-term nitrate therapy for ischemic heart disease may cause drug tolerance which diminishes its beneficial effects; consequently, intermittent administration of nitrates is recommended. With this regimen, however, the potential occurrence of rebound angina during the nitrate-free intervals is a source of concern. SUBJECTS AND METHODS: We carried out a retrospective study of 606 patients to determine whether rebound angina occurred when conventional continuous nitrate administration was replaced by intermittent administration as part of a long-term therapy protocol for prior myocardial infarction. The subjects were receiving treatment for myocardial infarction and included 293 patients treated with nitrates (Nitrate group) and 313 patients who were not (No-nitrate group). The former included 186 patients who received intermittent nitrate administration (Intermittent group) and 107 patients who received continuous administration (Continuous group). The mean period of observation was 4.3 +/- 1.6 months. RESULTS: There were no cases of rebound angina in the Intermittent group. Cardiac events occurred in one case in the No-nitrate group (0.3%), in 4 cases in the Continuous group (3.7%) and in 2 cases in the Intermittent group (1.1%). The incidence of cardiac events was thus significantly increased in the Continuous group compared to the No-nitrate group (p < 0.05; odds ratio 9.06; 95% CI 1.41-58.28). The Intermittent group did not significantly differ from the No-nitrate group in the incidence of cardiac events. CONCLUSION: It is concluded that intermittent administration of nitrates does not cause rebound angina and is therefore safe. A randomized controlled trial is needed to find the long-term effect on cardiac events.

Basic fibroblast growth factor increases regional myocardial blood flow and salvages myocardium in the infarct border zone in a rabbit model of acute myocardial infarction.

Basic fibroblast growth factor (bFGF) has been shown by some to promote angiogenesis and myocardial salvage in experimentally induced acute myocardial infarction. Although these findings have spurred much clinical interest, they are not universally observed, and the true efficacy of bFGF remains unclear. The authors used a rabbit model of acute myocardial infarction to further elucidate the effects of bFGF on acutely infarcted myocardium containing few collaterals. Myocardial infarction was evoked by ligation of the left coronary artery. Prior to ligation, either 100 microg of bFGF (bFGF group; n = 15) or physiological saline (control group; n = 22) was injected into the myocardium supplied by the ligated artery. With use of nonradioactive colored microspheres, regional blood flow (Qm) was measured before, immediately after, and 4 weeks after coronary artery ligation. Infarct and border zone sizes were measured in cross-sectional slices of the resected hearts, and the amount of viable myocardium (myocardium score) and the extent of fibrosis were histologically determined in each area. Four weeks after ligation, Qm values in the infarcted area did not significantly differ between the bFGF and control groups (0.54 +/- 0.36 vs 0.48 +/- 0.30 mL/min/g); in the border zone, Qm tended to be higher in the bFGF group (3.39 +/- 2.68 vs 1.47 +/- 0.80 mL/min/g), but the difference was not significant; finally in the noninfarcted area, Qm was significantly (p < 0.05) higher in the bFGF group (6.06 +/- 3.85 vs 2.09 +/- 0.82 mL/min/g). There was no significant difference in the amount of viable myocardium or the extent of fibrosis in the infarcted areas of the two groups. In the border zone, however, the amount of viable myocardium was significantly (p < 0.005) larger in the bFGF group (61.8 +/- 8.5% vs 35.8 +/- 20.3% of the visual field). Likewise, as graded on a scale from 0 to 5, the extent of fibrosis was significantly (p < 0.005) less in the bFGF group (2.1 +/- 0.5 vs 3.3 +/- 0.8). In conclusion, injection of bFGF into acutely infarcted myocardium increased blood flow to the noninfarcted area and salvaged the myocardium in the border zone.

Incidence of cancer in postmyocardial infarction patients treated with short-acting nifedipine and diltiazem. Secondary Prevention Group.

BACKGROUND: Recent reports suggest a possible link between nifedipine (but not diltiazem) and an increased risk of cancer in patients being treated with calcium antagonists. METHODS: A total of 1054 postmyocardial infarction patients were divided randomly into those being treated with calcium antagonists (n = 566 [nifedipine, 425 patients and diltiazem, 141 patients]) and controls (no calcium antagonist; n = 488). The patients were followed for 26.3 months, and the incidences of cardiac events as well as cancer were compared among the 3 groups. RESULTS: Thirteen patients (2.7%) in the control group developed cancer, whereas 15 patients in the nifedipine group (3.5%; odds ratio, 1.34; 95% confidence interval [95% CI], 0.63-2.85) and 3 patients in the diltiazem group (2.1%; odds ratio, 0.89; 95% CI, 0.27-2.93) developed cancer. CONCLUSIONS: Diltiazem appears to present no increased risk of cancer. The incidence of cancer was slightly higher in the patients receiving nifedipine than in those not being treated with a calcium antagonist, which is consistent with earlier reports; however, this increase was not statistically significant.

Asymmetric reduction of hydroxyacetone to propanediol in immobilized halotolerant microalga Dunaliella parva.

Cells of the halotolerant microalga Dunaliella parva immobilized in calcium-alginate gel showed morphological characteristics and photosynthetic activity similar to those of free cells. The photosynthetic activity in immobilized cells fell only about 20% during 2 weeks incubation at 5 degrees C in the light. The asymmetric reduction of hydroxyacetone to (R)-propanediol was first examined in batch reactions with both free and immobilized cells. Since the activity of immobilized cells was as high as that of free cells, the optimum conditions for the column reactor were investigated using immobilized cells. The productivity of propanediol in immobilized cells increased in proportion to increases in the light intensity, suggesting that NADPH regenerated through photosynthesis was used for the asymmetric reduction. Electron microscopic observation of thin sections of immobilized cells after the reaction suggested that NADPH used for asymmetric reduction in the dark was produced through the metabolism of starch granules. The use of a CaCO3-free medium in the column reactor markedly prolonged the period of reductive activity and photosynthesis.

Basic fibroblast growth factor increased regional myocardial blood flow and limited infarct size of acutely infarcted myocardium in dogs.

Basic fibroblast growth factor (bFGF), a growth factor potent in promoting angiogenesis, has been shown to reduce infarct size in experimentally induced acute myocardial infarction. However, the effect of bFGF on regional myocardial blood flow (Qm) in the acutely infarcted myocardium has not been well clarified. In 20 open-chest dogs, the left anterior descending (LAD) coronary artery was occluded and animals were maintained in this condition for 4 weeks. In eight of these dogs, bFGF (300 microg) was injected into the myocardium supplied by the LAD and the artery was ligated (bFGF group), and in the other 12 dogs, saline was injected (control group). Nonradioactive colored microspheres were used to measure Qm. The amount of viable myocardium as percent of visual field in the microscope and the extent of fibrosis scored histologically from 0 to 5 in the infarcted area 4 weeks after occlusion were measured. In the outer layer, the Qm values immediately after and 4 weeks after occlusion were 26 +/- 2% and 70 +/- 6%, respectively, in the control group, and 46 +/- 5% and 121 +/- 13%, respectively, in the bFGF group. The Qm at both times in the bFGF group was significantly higher than the corresponding control group values (p < 0.01). The Qm at 4 weeks in the inner and the middle layers also significantly increased in the bFGF group. There was more viable myocardium (control vs bFGF group; 41 +/- 5 vs 61 +/- 7%, p < 0.05) and less fibrosis (3.1 +/- 0.2 vs 2.0 +/- 0.4, p < 0.01) at the outer layer in the bFGF group. It was found that bFGF caused a marked increase in Qm, an increase of viable myocardium, and a decrease of fibrosis in the infarcted myocardium in dogs.