p53 mutations in non-small cell lung cancer in Japan: association between mutations and smoking.

The p53 gene has been implicated as a tumor suppressor gene involved in the pathogenesis of lung cancer. Our previous study revealed that the p53 gene is frequently mutated with a distinct nucleotide substitution pattern in small cell lung cancer specimens in Japanese patients. In this study, we examined 30 primary, resected non-small cell lung cancer samples in Japanese patients using complementary DNA-polymerase chain reaction and sequencing. Mutations changing the p53 coding sequence were found in 14 of 30 tumor samples (47%), while G:C to T:A transversions which are uncommon in other cancers such as colon cancer were the most frequently observed mutations, in agreement with an earlier report on non-small cell lung cancer in American patients. Furthermore, the present study shows for the first time that in univariate and multivariate analyses, the presence of p53 mutations is closely associated with lifetime cigarette consumption.     

Inhibitory effect of calcium chloride on gastric carcinogenesis in rats after treatment with N-methyl-N'-nitro-N-nitrosoguanidine and sodium chloride.

The effects of calcium chloride on glandular stomach carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and sodium chloride were investigated in male outbred Wistar rats. Animals were given MNNG solution (100 p.p.m.) as drinking water and simultaneously fed a diet supplemented with 5% sodium chloride for 8 weeks. Matched negative controls received neither MNNG nor sodium chloride. Rats were then fed basal diet and given calcium chloride solution (1 or 0.2%) or tap water for the following 52 weeks. The incidences and multiplicities of preneoplastic hyperplasias in the glandular stomachs of rats given MNNG/sodium chloride followed by 1 and 0.2% calcium chloride were significantly lower than those in rats given MNNG/sodium chloride alone. The inhibitory effects of calcium were exerted in a dose-dependent manner. Calcium treatment also showed a tendency to inhibit the development of gastric adenocarcinomas although this was not statistically significant. Rats without carcinogen treatment had neither carcinomas nor preneoplastic hyperplasias in the glandular stomach. Calcium intake also significantly reduced the levels of malondialdehyde, a measure of lipid peroxidation, in the gastric mucosa and urine, the former in a dose-dependent manner. Thus, calcium chloride exerted inhibitory effects when given during the post-initiation phase of two-stage glandular stomach carcinogenesis in rats.     

Epirubicin is equivalent to adriamycin in vitro against many cancer cells but more effective against gastric cancer cells.

We compared the cytotoxic effects of two anthracycline derivatives, epirubicin (EPI) and adriamycin (ADM), against human tumor cells in vitro. Various tumor specimens, obtained at surgery, included 57 liver, 19 lung, 16 gastric, 10 colorectal and 7 breast cancer specimens. These tumor cells were exposed to the same concentration of EPI or ADM for 3 days. The chemosensitivity of each tumor cell type to each drug was then assayed using the in vitro succinate dehydrogenase inhibition (SDI) test. Sensitivity to the treatment was defined as a 50% or greater reduction in the succinate dehydrogenase (SD) activity of the tumor cells, relative to that of the control (untreated) cells. Each cell type, except for gastric cancer cells, was equally sensitive to EPI and ADM. Gastric cancer cells were more sensitive to EPI than to ADM (P less than 0.05). The rate of coincidence, the sum of the co-sensitive and co-resistant rates of all the tumors, was quite high (90.8%). Thus, these findings indicate that EPI and ADM are equally cytotoxic to each tumor cell type, but EPI is more cytotoxic than ADM to gastric cancer cells. Since EPI is reported to be less cardiotoxic than ADM, EPI may replace ADM in cancer chemotherapy.     

Effects of caffeine, nicotine, ethanol and sodium selenite on pancreatic carcinogenesis in hamsters after initiation with N-nitrosobis(2-oxopropyl)amine.

The modulating effects of caffeine, nicotine, ethanol and sodium selenite on development of N-nitrosobis(2-oxopropyl)-amine (BOP)-initiated pancreatic tumors were investigated. Female Syrian golden hamsters were given s.c. injections of BOP (10 mg/kg body weight) or saline alone once a week for 3 weeks and then administered 2000 p.p.m. caffeine, 25 p.p.m. nicotine, 20% ethanol or 4 p.p.m. sodium selenite in their drinking water for the next 37 weeks. Control animals were given tap water alone after BOP initiation. Only the BOP-treated groups developed pancreatic adenocarcinomas and dysplasias. The multiplicity of pancreatic carcinomas was significantly higher (P less than 0.05) in animals receiving caffeine than in the controls. In addition, caffeine treatment slightly increased the incidence of carcinomas. Nicotine and ethanol also showed tendencies to enhance pancreatic carcinogenesis, although there were statistically no significant differences regarding lesion development. In contrast, sodium selenite administration was associated with a tendency for a decrease in the number of carcinomas and dysplasias. Thus, among these chemicals of obvious significance to human life-style, caffeine enhanced the development of pancreatic tumors when administered during the post-initiation phase in this hamster model.     

Immunohistochemical and biochemical identification of pepsinogen isozymes in the hamster lungs: induction by polychlorinated biphenyls.

Pepsinogens are acid protease enzymes of pepsin usually found in gastric mucosa. In the present study, we demonstrated the presence of pepsinogen isozymes in male Syrian golden hamster lung tissues by a combined immunohistochemical and biochemical approach. Immunohistochemically, using rat pepsinogen 1 antibody, pepsinogen positive cells were observed mainly in the epithelia of the terminal bronchioles. They demonstrated morphological features of Clara cells. The pepsinogen isozyme pattern of lung tissue determined by polyacrylamide gel electrophoresis was similar to that of stomach mucosa. Treatment of hamsters with polychlorinated biphenyls at a dose of 500 mg/kg body weight ip caused a 2.8-fold increase in pepsinogen content (p less than 0.01) as well as increase in numbers of pepsinogen positive cells in the lung.     

Pharmacokinetics of fluorinated 2-nitroimidazole hypoxic cell radiosensitizers in murine peripheral nervous tissue.

We have previously reported that KU-2285, a 2-nitroimidazole with a fluorinated N1-substituent (-CH2-CF2CONH(CH2)nOH, n = 2), was a promising hypoxic cell radiosensitizer. In this study the pharmacokinetics of KU-2285 and its related compounds (n = 3 and n = 4) were compared with those of etanidazole (a 2-nitroimidazole with an N1-substituent of -CH2CONH(CH2)nOH, n = 2) and its related compounds (n = 3 and n = 4) to assess the effects of incorporation of a CF2 group. The lipophilicity of the fluorinated compounds was higher than that of etanidazole, as measured by the octanol/water partition coefficient. As the number of CH2 groups increased, the lipophilicity of the compounds in both the KU-2285 and etanidazole series increased. The brain tissue levels of the fluorinated compounds were as low as those of the etanidazole derivatives, while the biological half-lives of the fluorinated compounds in peripheral nervous tissues were shorter than those of related non-fluorinated compounds.     

Thoracoscopic closure of a congenital partial pericardial defect

We describe our technique for performing direct thoracoscopic closure of a congenital partial pericardial defect, which was successfully employed in a 15-year-old boy. This is the first such report of a procedure that is noninvasive and may therefore become the treatment of choice for patients with a small congenital pericardial defect.