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B Rigas

Publications and source records attributed to B Rigas.

At least 19 recordsLinked to original sources
PubMed2005

Molecular targets of nitric-oxide-donating aspirin in cancer.

Nitric-oxide-donating aspirin (NO-ASA), consisting of ASA (aspirin) plus an -ONO2 moiety linked to it via a molecular spacer, is a new drug for cancer prevention. NO-ASA seems to overcome the low potency and toxicity of traditional ASA. The -ONO2 moiety is responsible for releasing NO, and it appears to be required for biological activity. In studies in vitro, NO-ASA inhibits the growth of colon, pancreatic, prostate, lung, skin, leukaemia and breast cancer cells, and is up to 6000-fold more potent than traditional ASA. This effect is owing to cell kinetics [inhibition of proliferation, induction of apoptosis (multiple criteria) and blocking the G1 to S cell-cycle transition] and cell signalling [inhibition of Wnt signalling (IC50=0.2 microM), inhibition of NF-kappaB (nuclear factor kappaB) activation (IC50=7.5 microM), inhibition of nitric oxide synthase-2 expression (IC50=48 microM), inhibition of MAPK (mitogen-activated protein kinase) signalling (IC50=10 microM) and induction of cyclo-oxygenase-2 at approx. 10 microM]. In studies in vivo, NO-ASA inhibits intestinal carcinogenesis in Min mice (tumour multiplicity was reduced by 59% after 3 weeks, with no effect in control animals and no side effects) and in the N-nitrosobis(2-oxopropyl)amine model of pancreatic cancer, where there was an 89% reduction in NO-ASA (3000 p.p.m. in the diet)-treated animals (P<0.001). There was no statistically significant effect by traditional ASA at equimolar doses. Our data indicate that NO-ASA is a highly promising agent for the prevention and/or treatment of cancer.

Animals↗
PubMed2005

Is COX-2 a 'collateral' target in cancer prevention?

NSAIDs (non-steroidal anti-inflammatory drugs) prevent colon and other cancers. The fact that NSAIDs inhibit the eicosanoid pathway prompted mechanistic drug-developmental work focusing on COX (cyclo-oxygenase) and its products. The increased prostaglandin E2 levels and the overexpression of COX-2 in colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention or treatment. However, one COX-2 inhibitor has been withdrawn from the market because of cardiovascular side effects, and there are concerns about a class effect. Evidence suggests that COX-2 may not be the only, or the ideal, target for cancer prevention; for example, COX-2 is not expressed in human aberrant crypt foci, the earliest recognizable pre-malignant lesion in the colon; COX-2 is expressed in less than half of the adenomas; in vitro data show that NSAIDs do not require the presence of COX-2 to prevent cancer; in familial adenomatous polyposis, the COX-2 inhibitor, celecoxib, had a modest effect, which was weaker than that of a traditional NSAID; and COX-2-specific inhibitors have several COX-2-independent activities, which may account for part of their cancer-preventive properties. The multiple COX-2-independent targets, and the limitations of COX-2 inhibitors, suggest the need to explore targets other than COX-2.

Adenomatous Polyposis Coli↗
PubMed2003

NO-NSAIDs and cancer: promising novel agents.

Three potential applications of NO-donating NSAIDs in human cancer include their use: as chemopreventive agents; against already developed cancers (chemotherapy); and for the control of cancer symptoms, notably cancer pain. The evidence to date of greater safety and enhanced efficacy of NO-donating NSAIDs underscores their potential to prevent colon cancer and overcome the limitations of traditional NSAIDs. NO-donating NSAIDs affect several pathways critical to colon carcinogenesis and this may explain in part their greater efficacy in colon cancer prevention as assessed in preclinical models.

Animal Experimentation↗
PubMed2001

Effect on treatment outcome of coinfection with SEN viruses in patients with hepatitis C.

The newly discovered SEN D and SEN H viruses are transmitted parenterally and can cause post-transfusion hepatitis. We assessed whether coinfection of patients with chronic hepatitis C and SEN D or SEN H correlates with the outcome of treatment with interferon and ribavirin. Of 31 patients with hepatitis C studied, six were positive for SEN D and seven for SEN H (one was positive for both). All of those positive for SEN D and five of those positive for SEN H failed to respond to therapy. Overall response (RNA titre and alanine aminotransferase concentration after treatment) was lower in SEN-infected patients than uninfected patients (p=0.025). We conclude that coinfection with SEN viruses is frequent in chronic hepatitis C patients and might adversely affect the outcome of treatment with interferon and ribavirin.

Alanine Transaminase↗
PubMed2001

Decreased expression of DNA-dependent protein kinase, a DNA repair protein, during human colon carcinogenesis.

DNA-dependent protein kinase (DNA-PK), consisting of a catalytic subunit (DNA-PKcs) and the Ku70 and Ku86 proteins, participates in the repair of DNA double-strand breaks (DSBs). We assessed its expression immunohistochemically in normal human colon tissue, colon adenomas, colon carcinomas, and normal tissue distant from carcinomas. Normal colonocytes expressed all DNA-PK proteins. Compared with the expression in normal tissue [176.62 +/- 18.56 (the intensity of expression x the percentage of cells expressing this protein), mean + SE], the expression of Ku70 was significantly reduced in adenomas (36.62 +/- 11.09; P < 0.001) and carcinomas (85.68 +/- 15.76; P < 0.01), as was the expression of Ku86 [(113.10 +/- 10.22 versus 41.66 +/- 14.71 in adenomas (P < 0.01) or versus 85.68 +/- 15.76 in carcinomas (P < 0.05)]. The expression of DNA-PKcs was not significantly changed. The marked underexpression of Ku70 and Ku86 starting at the adenoma stage may be crucial to the development of colon cancer.

Adenoma↗
PubMed2001

Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) alter the kinetics of human colon cancer cell lines more effectively than traditional NSAIDs: implications for colon cancer chemoprevention.

Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAIDs), consisting of a known nonsteroidal anti-inflammatory drug (NSAID) and a nitric oxide (NO)-releasing group, are reported safer than NSAIDS: To assess their potential in colon cancer chemoprevention, we studied in vitro the effect of NO-aspirin, NO-sulindac, and NO-ibuprofen on colonocyte kinetics. These three NO-NSAIDs reduced the growth of cultured HT-29 colon adenocarcinoma cells much more effectively than the corresponding NSAIDs; e.g., at 24 h, their IC(50) values were as follows: (a) aspirin, >5000 microM; (b) NO-aspirin, 1 microM; (c) sulindac, 750 microM; (d) NO-sulindac, 150 microM; (e) ibuprofen, >1000 microM; and (f) NO-ibuprofen, 42 microM. This effect was due to inhibition of proliferation and induction of apoptosis and perhaps to the induction of novel cell changes, characterized by extensive DNA degradation. NO-NSAIDs also blocked the G(0)-G(1) to S cell cycle transition. Their superior effectiveness compared with traditional NSAIDs, combined with their reported safety, makes them promising candidates for chemopreventive agents against colon cancer.

Adenocarcinoma↗
PubMed2001

The retinoid fenretinide inhibits proliferation and downregulates cyclooxygenase-2 gene expression in human colon adenocarcinoma cell lines.

Fenretinide [N-(4-Hydroxyphenyl)retinamide, 4-HPR] (10(-10)-10(-6) M) treatment of HT-29 human colon cancer cells for 24-72 h significantly inhibited their growth. Using HCT-15 cells, 4-HPR had limited inhibitory effects on cell proliferation over the same concentration range and time period. The inhibitory effects of 4-HPR on cell growth in HT-29 cells were markedly reduced in the presence of exogenously added prostaglandins (PGs), suggesting a possible role for inhibition of PG synthesis as a mechanism for 4-HPR's antiproliferative effects. Inhibition of PGE(2) production was caused by 4-HPR in a concentration-dependent manner and decreased COX-2 but not COX-1 mRNA levels; this is the first indication that 4-HPR selectively inhibits COX-2 gene expression. Our findings suggest a possible mechanism for the chemopreventive and anti-proliferative effects of 4-HPR.

Adenocarcinoma↗
PubMed2000

Altered gastric epithelial cell kinetics in Helicobacter pylori-associated intestinal metaplasia: implications for gastric carcinogenesis.

We have compared apoptosis and proliferation in antral epithelium from individuals not infected with H. pylori (Hp), those with Hp-induced gastritis and those with Hp-induced gastritis containing areas of gastric intestinal metaplasia, the precursor lesion to gastric adenocarcinoma. Antral biopsies from 42 patients were assessed for evidence of Hp infection, severity of gastritis and intestinal metaplasia. Apoptosis was evaluated by the TUNEL assay and proliferation by Ki-67 immunohistochemistry and were expressed as apoptotic (AI) and proliferation (PI) indices. In the 31 Hp-positive (Hp(+)) patients, apoptosis and proliferation were increased compared with the 11 Hp-negative (Hp(-)) patients (AI = 1. 22 +/- 0.13% vs. 0.15 +/- 0.03%, p < 0.0001; PI = 24 +/- 1% vs. 13 +/- 2%, p < 0.0001). Increases were proportional to the severity of the inflammation. Within foci of intestinal metaplasia, in 9 of the Hp(+) patients, apoptosis was significantly reduced compared with surrounding gastritis (AI = 0.20 +/- 0.06% vs. 1.34 +/- 0.23%, p = 0. 0014), whereas proliferation was not altered (PI = 25.4 +/- 4% vs. 24.7 +/- 2%, p = 0.87), resulting in a lower AI/PI ratio in intestinal metaplasia than in surrounding gastritis (0.008 +/- 0.005 vs. 0.054 +/- 0.009, p < 0.02). Hp-induced gastritis is thus associated with increased epithelial apoptosis and proliferation compared with uninfected controls. In intestinal metaplasia, proliferation remains increased but apoptosis reverts to normal levels, and this perhaps contributes to Hp-associated gastric carcinogenesis.

Adolescent↗
PubMed2000

Infrared spectroscopic study of cervical smears in patients with HIV: implications for cervical carcinogenesis.

Patients with HIV have an increased incidence of cervical cancer, necessitating increased surveillance. Infrared spectroscopy (IRS) has the potential of aiding the diagnosis of cervical neoplasia and also of providing clues into its pathogenesis. We studied by IRS cervical scrapings from 22 HIV-infected and 23 control women; 8 of the former and none of the latter had dysplasia. The infrared spectra followed three patterns, designated pattern I (similar to that previously associated with normal cervical samples), pattern II (intermediate between patterns I and III), and pattern III (associated with cervical neoplasia). Compared with HIV-negative controls, HIV-infected women had a higher prevalence of pattern III and a lower prevalence of pattern II; these differences were statistically significant (P = .015 by chi2 analysis). Similar spectroscopic changes were present even when only the cytologically normal samples from HIV-positive and HIV-negative women were analyzed. We speculate that these changes may reflect early structural changes associated with cervical neoplasia that are not detectable cytologically. The infrared spectra in the region 950 to 1,300 cm(-1) could not differentiate cervical samples from HIV-infected and uninfected patients. The potential practical applications of IRS in HIV cervical disease are discussed.

Adenocarcinoma↗
PubMed2000

Is inhibition of cyclooxygenase required for the chemopreventive effect of NSAIDs in colon cancer? A model reconciling the current contradiction.

NSAIDs are powerful chemopreventive agents for colon cancer, but their mechanism of action remains unknown. Their best recognized pharmacological property is inhibition of the enzyme cyclooxygenase (COX), which catalyzes the synthesis of prostaglandins; however, additional effects are well documented. Current studies on the mechanism of the chemopreventive effect of NSAIDs lead to two contradictory conclusions: NSAIDs prevent colon cancer either by inhibiting the activity of COX, or through mechanisms that do not require COX inhibition. To resolve this apparent conflict, after examining several alternatives, we propose a model, which assumes that both mechanisms are correct but that they exert their effect either on different steps of the multistep process of colon carcinogenesis or on different control mechanisms. This postulated dual action of NSAIDs may explain their remarkable effectiveness in colon cancer prevention. Unraveling these mechanistic details can be very rewarding for the design of more refined approaches to cancer chemoprevention and for a deeper understanding of colorectal carcinogenesis.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

The effect of lithocholic acid on proliferation and apoptosis during the early stages of colon carcinogenesis: differential effect on apoptosis in the presence of a colon carcinogen.

Lithocholic acid (LCA) is implicated in human and experimental animal carcinogenesis. Its effect on apoptosis and proliferation of the colonic epithelium was studied in a 1,2-dimethylhydrazine (DMH)-induced murine carcinogenesis model. Four groups of mice, control, LCA, DMH and DMH+LCA, were studied for 4 weeks, a period corresponding to early stages of carcinogenesis. Apoptosis (AI) and proliferation (PI) indices in the colon were determined by immunohistochemistry. LCA stimulated apoptosis [AI = 1.2 +/- 0.3% (all values are the mean +/- SEM) versus control 0.5 +/- 0.1%, P < 0. 05], as did DMH (4.3 +/- 0.8%, P < 0.02). DMH increased apoptosis at the base of the crypt nearly 50-fold, with no effect at the lumenal third. In mice receiving DMH, LCA suppressed apoptosis almost completely (0.1 +/- 0.03%); this suppression was complete at the lower two-thirds of the crypt (AI = 0) and 60% at the lumenal third. LCA increased proliferation (PI = 22.2 +/- 4.6% versus 15.4 +/- 1% in controls), but this did not reach statistical significance. DMH increased proliferation (PI = 34.6 +/- 2.3%, P < 0.01). In mice receiving DMH, proliferation (41 +/- 2.9%) was about two-thirds of the additive effect. LCA affected proliferation, mainly in the middle third of the crypt; DMH's effect was similar in distribution, but more pronounced. In mice receiving DMH, LCA shifts proliferation upward, extending it to the lumenal third of the crypt. LCA's main cell kinetic effect in the colon is on apoptosis; this effect differs in normal (stimulation) and pre-malignant colon (nearly complete suppression). LCA does not significantly stimulate proliferation in either normal or pre-malignant colon. The differential effect of LCA on apoptosis in the presence of a carcinogen partially explains its effect as a promoter on colon carcinogenesis in animal models, and may have important implications for human carcinogenesis.

Animals↗
PubMed1999

Nonsteroidal anti-inflammatory drugs and the induction of apoptosis in colon cells: evidence for PHS-dependent and PHS-independent mechanisms.

NSAIDs are potent chemopreventive agents for colon cancer. Although their mechanism of action is unknown, it probably relates to their modulation of colon epithelial cell kinetics, i.e. apoptosis and/or cell proliferation. NSAIDs are pleiotropic in their biochemical activities; their best known effect is inhibition of prostaglandin H synthase (PHS), the enzyme catalyzing the biosynthesis of prostaglandins. Current data appear to lead to two conflicting conclusions. One body of data indicates that PHS is important in induction of apoptosis and colon carcinogenesis and that its inhibition by NSAIDs is required for induction of apoptosis and their overall chemopreventive effect. Another set of data indicates that NSAIDs may induce apoptosis and prevent colon cancer without inhibiting the activity of PHS. Both sides of this argument are presented and discussed. This apparent contradiction may be resolved if one accepts that both mechanisms are correct but that they act on different steps of this multistep process.

Journal Article↗
PubMed1999

Role of diet and NSAIDs in the chemoprevention of colorectal cancer.

Colorectal cancer is a major public health problem. It is also one of the most preventable cancers. Although the colorectal cancer incidence and mortality in whites have been declining over the past 2 decades, these statistics are rising in nearly all ethnic minority groups. The development of colorectal cancer is influenced by exogenous factors, such as dietary constituents and drugs. While reputable data on the chemopreventive effects of diet and drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), in specific minority groups are limited, evidence suggests that dietary factors may affect colorectal carcinogenesis in various ethnic minority groups. Clearly, more studies are necessary to resolve these questions. Because the risk of colorectal cancer is increasing in minority patients, they cannot wait for the results of such studies. Therefore, until definitive data are available, it is prudent for physicians to recommend that all individuals be screened for colorectal cancer according to accepted guidelines and to educate them regarding healthful eating habits that will prevent the development of colorectal cancer. Physicians should be particularly vigilant in recommending these approaches to minority patients. Patients should be advised to consume a well-balanced, low-fat, high-fiber diet that is rich in fruits and vegetables.

Black or African American↗
PubMed1998

Cytologically normal cells from neoplastic cervical samples display extensive structural abnormalities on IR spectroscopy: implications for tumor biology.

Fourier-transform IR (FT-IR) spectra of pelleted exfoliated cervical cells from patients with cervical cancer or dysplasia differ from those from normal women. To study the origin of these spectral changes, we obtained the FT-IR spectra of individual cervical cells from normal, dysplastic, and malignant cervical samples. Ninety five percent of normal superficial and intermediate cells displayed two distinct spectral patterns designated A and B, and 5% displayed an intermediate pattern, suggesting extensive structural heterogeneity among these cells. Parabasal and endocervical cells showed pattern B spectra. The spectra of malignant, dysplastic, and other abnormal cells also were characterized. Analysis of FT-IR spectra of over 2, 000 individual cells from 10 normal females, 7 females with dysplasia, and 5 females with squamous cell carcinoma revealed that the spectra of normal-appearing intermediate and superficial cells of the cervix from women with either dysplasia or cancer differed from those of normal women. Chemometric and classical spectroscopic analysis showed a continuum of changes paralleling the transition from normalcy to malignancy. These findings suggest that (i) the structural changes underlying the spectroscopic changes are involved in or are a product of cervical carcinogenesis and (ii) the neoplastic process may be more extensive than currently recognized with morphological criteria. This approach may be useful for the structural study of neoplasia and also may be of help in the diagnosis or classification of cervical disorders.

Adult↗