Embryotoxicity of acrolein,acrylonitrile and acryl-amide in developing chick embryos

The embryotoxicity of acrolein, acrylonitrile and acrylamide was studied in chicken eggs treated on day 3 and examined on day 14 of incubation. The approximate LD₅₀ values were estimated to be 0.05, 2.5 and 5 μmoles/egg, respectively. The embryos were examined for macroscopic malformations but no evidence on induced teratogenicity was observed.     

Assessment of catechol induction and glucuronidation in rat liver microsomes.

Catechols are substances with a 1,2-dihydroxybenzene group from natural or synthetic origin. The aim of this study was to determine whether catechols (4-methylcatechol, 4-nitrocatechol, 2,3-dihydroxynaphthalene) and the antiparkinsonian drugs, entacapone and tolcapone, at doses 150 to 300 mg/kg/day, for 3 days, are able to enhance their own glucuronidation. The induction potency of catechols on rat liver UDP-glucuronosyltransferases (UGTs) was compared with that of a standard polychlorinated biphenyl (PCB) inducer, Aroclor 1254. The glucuronidation rate of these catechols was enhanced up to 15-fold in the liver microsomes of PCB-treated rats, whereas treatment with catechols had little effect. Entacapone, tolcapone, 4-methylcatechol, catechol, 2,3-dihydroxynaphthalene, and 4-nitrocatechol were glucuronidated in control microsomes at rates ranging from 0.12 for entacapone to 22.0 nmol/min/mg for 4-nitrocatechol. Using 1-naphthol, entacapone, and 1-hydroxypyrene as substrates, a 5-, 8-, and 16-fold induction was detected in the PCB rats, respectively, whereas the catechol-induced activities were 1.1- to 1.5-fold only. Entacapone was glucuronidated more efficiently by PCB microsomes than by control microsomes (Vmax/Km, 0.0125 and 0.0016 ml/min/mg protein, respectively). Similar kinetic results were obtained for 1-hydroxypyrene. The Eadie-Hofstee plots suggested the contribution of multiple UGTs for the glucuronidation of 1-hydroxypyrene (Km1, Km2, Km3 = 0.8, 9.7, and 63 microM, and Vmax1, Vmax2, Vmax3 = 11, 24, and 55 nmol/min/mg, respectively), whereas only one UGT could be implicated in the glucuronidation of entacapone (Km = 130 microM, Vmax = 1.6 nmol/min/mg). In conclusion, catechols are poor inducers of their own glucuronidation supported by several UGT isoforms. Their administration is unlikely to affect the glucuronidation of other drugs administered concomitantly.     

Contact allergy to corticosteroids in asthma/rhinitis patients

Patients with asthma and/or rhinitis, when using inhalers or nasal sprays containing corticosteroids, may experience mucosal symptoms, such as congestion of the nose, itching, nose bleeding and worsening of rhinitis, but also eczema of the face sometimes spreading to flexures, and sometimes the corticosteroid simply does not help. Few patients with such symptoms have been found to be allergic to their inhaled corticosteroids (1), and no report on whether contact allergy to corticosteroids could explain treatment failures is available. This issue was investigated in 2 ways: (i) by testing asthma/rhinitis patients for corticosteroid allergy, (ii) by looking at the prevalence of tixocortol pivalate allergy among dermatitis patients with and without asthma/rhinitis, respectively.     

NY-ESO-1 protein expression and humoral immune responses in prostate cancer

BACKGROUND: Due to restricted expression in normal tissues cancer/testis (C/T) antigens represent candidate molecules for immunotherapy of cancer. NY-ESO-1 is a well-studied C/T antigen with unknown expression and immunogenicity in prostate cancer (PC) patients. METHODS: NY-ESO-1 expression was determined by immunohistochemistry and humoral immune responses against NY-ESO-1 assessed by enzyme-linked immuno-sorbent assay (ELISA) and Western blotting. Protein expression and serological responses were correlated with clinical findings and survival. RESULTS: NY-ESO-1 expression was found in biopsies from 2 of 66 localized PC and 7/48 hormone refractory prostate cancer (HRPC) patients, respectively. Anti-NY-ESO-1 antibodies were detected in sera from 1 of 112 localized PC and 18 of 95 HRPC patients. Two of four HRPC patients with NY-ESO-1 positive biopsies had mounted a serological response. Positive anti-NY-ESO-1 titers were correlated with poor survival in HRPC patients. CONCLUSIONS: NY-ESO-1 is expressed in a subset of HRPC patients and, together with other C/T antigens, may serve as a target antigen for development of immunotherapy of PC. Spontaneous serological responses against NY-ESO-1 may be associated with poor survival.     

Methylation of cytochrome P4501A1 promoter in the lung is associated with tobacco smoking

Cytochrome P4501A1 (CYP1A1), which is involved in the metabolic activation of polycyclic aromatic hydrocarbon procarcinogens derived from tobacco smoke, is induced in the lung up to 100-fold because of tobacco smoking. Our aim was to study whether promoter methylation has any role in the smoking-associated expression of CYP1A1 in human lung. Methylation of CpG sites up to 1.4 kb upstream of CYP1A1 gene was studied first by sequencing. Because methylation was observed between nucleotides -1400 and -1000, a methylation-specific single-strand conformational polymorphism method was designed for the region between nucleotides -1411 and -1295 that contains five potential methylation sites, one of them at the xenobiotic responsive element core sequence. Single-strand conformational polymorphism was used on DNA from normal lung samples and peripheral WBCs of smokers and nonsmokers, and on human lung adenocarcinoma (A549) and bronchial epithelial (Beas-2B) cell lines. In lung tissue complete or partial methylation occurred in 33% of heavy smokers (>15 cigarettes/day, n = 30), 71% of light smokers (< or =15 cigarettes/day or quitted 1-7 days earlier, n = 42), and in 98% of nonsmokers (never and ex-smokers, n = 49). Methylation was found to increase in 1-7 days after quitting smoking. In active smokers the lack of methylation in the studied region of CYP1A1 promoter was associated with a slightly higher pulmonary 7-ethoxyresorufin O-deethylase activity in the regression models allowing for the daily tobacco consumption and age. No association was observed in WBC between methylation and tobacco smoking. In lung-derived cell lines the methylation remained stable regardless of induction with benzo(a)pyrene, but a higher induction was observed in Beas-2B cells, which also had less methylation than A549 cells. The association of tobacco smoking with CYP1A1 methylation in the lung suggests that promoter methylation is involved in the regulation of CYP1A1 induction in vivo.     

Androgen-independent prostate cancer--the clinical problem of a growing pelvic tumour

This retrospective study describes three clinically different groups of patients with symptomatic androgen-independent prostate cancer (AIPC) referred to palliative radiotherapy (RT): those with a symptomatic pelvic tumour and pelvis-confined disease (M0 P-RT: 35 patients), those with a symptomatic pelvic tumour and distant metastases (M + P-RT: 97 patients) and those with painful bone metastases (BM-RT: 193 patients). The study emphasises the need of a combined surgical and radiotherapeutic palliation in AIPC patients with symptomatic pelvic tumours. Median overall survival from time of palliative RT was 19, 9 and 8 months for M0 P-RT, M + P-RT and BM-RT patients, respectively (p < 0.001). The significantly prolonged natural course of P-RT patients without distant metastases has to be accounted for in clinical trials of AIPC patients in whom survival represents an endpoint. Furthermore, the optimal palliation regimens for P-RT patients are still to be defined.