Increased frequency of wild-type arylamine-N-acetyltransferase allele NAT2*4 homozygotes in Portuguese patients with colorectal cancer

Here we report that colorectal cancer patients show a markedly higher frequency (3-fold) of wild-type NAT2*4 allele homozygotes than the control population. However, a marked difference in NAT2*4/NAT2*4 genotype frequency associated with the patients gender was observed pointing to a male-specific effect of this genotype as a risk factor in colon cancer. The arylamine-N-acetyltransferase (E.C. 2.3.1.5.) NAT2, a phase II detoxification enzyme, has been implicated in procarcinogen activation, namely from food contained arylamines, cigarette smoking, as well as environmental amines of various types. NAT2 is encoded by a polymorphic gene presenting several allelic variants encoding partially inactive enzymes expressed in human liver and colon. Epidemiological studies based on phenotype determination have long indicated the importance of the NAT2 active phenotype as a susceptibility factor in colorectal cancer. In the present study we investigated the NAT2 allelic frequencies and genotype distribution in a group of 114 unrelated colorectal cancer patients, in parallel with 201 healthy Portuguese subjects. We first demonstrate that the frequency of the wild-type NAT2*4 allele in the Portuguese sample population (23.4%) does not significantly differ from the values described for other Europeans. Besides the 3-fold higher frequency of NAT2*4 homozygotes found in colorectal cancer subjects, the NAT2*4/NAT2*5A compound genotype, known to determine a faster acetylator phenotype than other heterozygotic combinations, also increased by the same order of magnitude. These two genotypes represent 32% of the patients population versus 11% of the healthy controls. Taken together, our results strongly indicate that NAT2 genotype, particularly NAT2*4 allele zygosity, constitutes an individual susceptibility trait associated with sporadic colorectal cancer development, probably due to the local dietary habits in Portugal.      

Contractile responses evoked by dihydroergotamine, naratriptan and sumatriptan in the canine isolated coronary artery

Summary— Contractile responses evoked by the 5-HT_1B/D receptor agonists, dihydroergotamine, naratriptan and sumatriptan, were compared in canine isolated coronary artery rings before and after endothelial dysfunction as obtained by inhibition of nitric oxide synthase with Nω-nitro-L-arginine methyl ester (L-NAME; 10 μM). The three agonists contracted rings in the potency order of dihydroergotamine (geometric mean pD₂ value with 95% confidence limits in parentheses: 6.9 [5.3–7.9] and 7.0 [5.4–7.3] in the absence and presence of nitric oxide synthase (NOS) inhibition [I], respectively) ≥ naratriptan (6.8 [5.7–7.3] and 6.4 [5.7–6.6]) > sumatriptan (4.8 [3.6–5.6] and 5.0 [3.6–5.6]) independently of the presence or absence of L-NAME. In absence of L-NAME, efficacy, as assessed by the mean maximal contractile response (Emax), tended to be greater, although not significantly, for sumatriptan and naratriptan compared to dihydroergotamine. L-NAME per se markedly increased developed tension (43.0 ± 4.6 mN; n = 50) and potentiated maximal responses (0.6 ± 0.2 and 10.7 ± 2.4 mN for dihydroergotamine in the absence and presence of L-NAME respectively; 1.7 ± 0.6 and 18.7 ± 3.7 mN for naratriptan; 2.5 ± 0.6 and 21.3 ± 3.8 mN for sumatriptan; P < 0.01 in each case). Emax values of sumatriptan and naratriptan were greater than those produced by dihydroergotamine in the presence of L-NAME but remained lower than the sub-maximal contractile responses evoked by the thromboxane A₂ analogue, U-46619 (ie, 32.4 ± 5.2 mN in the absence of L-NAME; n = 50), or L-NAME per se. In conclusion, 5-HT_1B/D receptor agonist efficacies in contracting coronary arteries are relatively low under basal conditions and are potentiated in the presence of a dysfunctional endothelium, whereas agonist potencies remain unaffected.     

苦参碱对细菌脂多糖诱导大鼠枯否细胞释放肿瘤坏死因子及白细胞介素-6的影响

目的是研究苦参碱对细菌脂多糖(lipopolysachrides,LPS)诱导经卡西霉素(calcimycin,Cal)预激活的大鼠枯否细胞分泌肿瘤坏死因子(tumor necrosis factor,TNF)、白细胞介素-6(interleukin-6,IL-6)的影响以及对小鼠体内产生TNF和IL-6的影响。结果,苦参碱125,250及500mg·L^-1剂量依赖性抑制大鼠枯否细胞分泌TNF和IL-6;苦参碱50及100mg·kg^-1降低小鼠体内TNF和IL-6的水平。提示苦参碱的抗炎作用可能与其抑制TNF及IL-6的产生有关。     

Omeprazole-amoxycillin versus omeprazole-amoxycillin-clarithromycin in the eradication of Helicobacter pylori.

AIM: To assess the effect of adding clarithromycin to the combination of omeprazole and amoxycillin for the eradication of H. pylori infection. PATIENTS AND METHODS: In an open, randomized, three-centre study 120 patients (69 men, mean age 47 years, caucasians 74%) with symptoms of dyspepsia had normal gastroscopic examination and a positive urease test. They underwent a 13C-urea breath test and received, for 14 days, either omeprazole 40 mg b.d. plus amoxycillin 750 mg b.d., or the same regimen plus clarithromycin 250 mg b.d. Compliance was assessed by returned tablet counts. H. pylori clearance at the end of treatment and eradication 4 weeks after finishing treatment were assessed by 13C-urea breath test. RESULTS: Results are expressed according to 'all patients treated analysis', excluding patients who did not receive treatment and patients who had no final 13C-urea breath test assessment. In the groups treated with omeprazole- amoxycillin or omeprazole-amoxycillin-clarithromycin good compliance (> or = 90%) was observed in 85% vs. 76% (N.S.) of patients but 25% vs. 34% (N.S.) experienced at least one adverse event. Adverse events were minor, and no patient reported a metallic taste. Four weeks after finishing treatment eradication rates were 26% (95% CI: 15-37%) vs. 93% (95% CI: 86-99%) (P < 0.001). CONCLUSION: These results show that dual therapy with omeprazole plus amoxycillin achieves an unacceptably low H. pylori eradication rate. Addition of clarithromycin at low dosage (250 mg b.d.) proved to be useful, achieving a high eradication rate without increasing side-effects.     

Le contrôle local de la tumeur primitive. Étape indispensable de la guérison des cancers

There is clear evidence for a cancer cure. The hypothesis behind a treatment with curative intent is the ability to eradicate all the cancer cells of a tumour. Out of three cancer deaths, one is related to local failure. In some cancers like breast carcinoma, death is mainly in relation with the development of distant metastases. Even in such a tumour, an improvement in local control can translate as better survival. Radiationtherapy, often in association with surgery, is playing a major role in tumour local control. Such a local control is mandatory if cure is at aim. One of the main goals of clinical research is to find a good compromise between local control of the disease and a non mutilating surgical approach.     

p53, but not p16 mutations in oral squamous cell carcinomas are associated with specific CYP1A1 and GSTM1 polymorphic genotypes and patient tobacco use

Inactivation of tumor suppressor genes like p53 and p16 play a key role in tumor progression, with a high incidence of mutations existing for both genes in oral squamous cell carcinomas. Previous studies have demonstrated, (i) a correlation between the prevalence of p53 mutations and tobacco use [Brennan et al. (1995) New Engl. J. Med., 332, 712-717; Lazarus et al. (1996) Carcinogenesis, 17, 733-739], and (ii) a link between genotypes in specific xenobiotic metabolizing enzymes and oral cancer susceptibility [Park et al. (1997) Cancer Epid. Biomarkers Prev., 6, 791-797). In this paper, we present results of our examination of a series of 80 oral squamous cell carcinomas for p53 exons 5-9 and p16 exons 1-2 mutations, and the potential association of these mutations with specific genotyping patterns. p53 mutation prevalence in oral tumors was linked with increased patient tobacco use using several stratification criteria. There was a significantly higher prevalence of p53 mutations in OCSCCs from patients who smoked > 30 pack-years as compared to tumors from patients who smoked < or = 30 pack-years (OR = 2.8; CI = 1.1-7.2). No significant association was observed with patient alcohol consumption. There was a significant association between the prevalence of p53 mutations in oral tumors and CYP1A1 genotyping patterns in these oral cancer patients, with the highest p53 mutation prevalence observed in subjects with the CYP1A1 [val]/GSTM1 [+] genotype (OR = 6.0; CI = 1.2-29.7). A significant association was not observed between the prevalence of p16 mutations in oral tumors and tobacco use, or CYP1A1 [val] or GSTM1 (0/0) genotypes. These data suggest that the induction of mutations in specific tumor suppressor genes or oncogenes in oral tumors may be associated with specific carcinogen exposures, and that this association may be linked to specific polymorphic genotypes in xenobiotic-metabolizing enzyme genes.