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Biomedical subjects

T Sugimura

Publications and source records attributed to T Sugimura.

At least 577 records · Page 32Linked to original sources
PubMed1987

Activation of N-ras gene in a rat hepatocellular carcinoma induced by dibutylnitrosamine and butylated hydroxytoluene.

DNA samples from eighteen rat hepatocellular carcinomas, including those induced by oral administration of dibutylnitrosamine (DBN) with butylated hydroxytoluene (BHT), or DBN with butylated hydroxyanisole (BHA), have been tested for the presence of transforming activity by transfection assay with NIH3T3 cells. Of the eighteen samples, only one from a tumor induced by DBN and BHT gave transformants. the activated oncogene was identified as rat N-ras by Southern blot analysis.

Animals↗
PubMed1987

Amino-acid substitution at codon 13 of the N-ras oncogene in rectal cancer in a Japanese patient.

The activation of proto-oncogenes in colorectal cancers in Japanese patients was studied using a mouse NIH3T3 cell transfection assay system. Of thirty-five colorectal cancers examined, one rectal cancer showed an unusually high transformation efficiency and, in this rectal cancer, the N-ras oncogene was found to be activated. Nucleotide sequence analysis of the activated N-ras showed a single G----C point mutation at the first letter of codon 13, resulting in the coding of arginine instead of glycine. This amino-acid substitution at codon 13 may be responsible for the efficient induction of transformants of NIH3T3 cells in vitro.

Animals↗
PubMed1987

Transforming activity of human c-Ha-ras-1 proto-oncogene generated by the binding of 2-amino-6-methyl-dipyrido[1,2-a:3',2'-d]imidazole and 4-nitroquinoline N-oxide: direct evidence of cellular transformation by chemically modified DNA.

An activity that transforms NIH 3T3 cells was generated by the in vitro modification of plasmids containing the human c-Ha-ras-1 proto-oncogene with the synthesized ultimate carcinogen, 2-acetoxyamino-6-methyldipyrido[1,2-a:3',2'-d]-imidazole (N-OAc-Glu-P-1). DNAs isolated from the transformed cells were analyzed by restriction fragment length polymorphism (RFLP) assay using the restriction enzyme Msp I. Of fourteen transformants studied, six contained a mutation in the region of the CCGG sequence of the eleventh and the twelfth codons, in which GG corresponds to the first two nucleotides of the twelfth codon. Transforming activity was also generated by the chemical modification of the plasmids with 4-acetoxyaminoquinoline N-oxide (N-OAc-4AQO). The results clearly indicate that formation of DNA adducts with N-OAc-Glu-P-1 or N-OAc-4AQO causes the induction of transformation of mammalian cells.

4-Nitroquinoline-1-oxide↗
PubMed1987

Presence of tumor promoters in the seed oil of Jatropha curcas L. from Thailand.

The seed oil of Jatropha curcas L. was shown to contain skin tumor promoters in a two-stage mouse carcinogenesis experiment. By using the irritant test on mouse ear to monitor activity, the "irritant fraction" was partially purified from the methanol extract of the seed oil by column chromatographies on Florisil and Sephadex LH-20. The irritant fraction obtained induced ornithine decarboxylase in mouse skin and inhibited the specific binding of 3H-12-O-tetradecanoylphorbol-13-acetate to a particulate fraction of mouse skin. After initiation with 7,12-dimethylbenz[a]anthracene (DMBA), this "irritant fraction" induced tumors in the skin of 36% of the mice tested in 30 weeks. Tumor incidences in the groups treated with DMBA alone and "irritant fraction" alone were 7% and 13% in week 30, respectively. Since the skin of Thai people comes into direct contact with this seed oil, an epidemiological study on human skin cancer in Thailand is indicated.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Y chromosome abnormality in human stomach and lung cancer.

Sex chromosome abnormalities in human stomach and lung cancers from 33 male patients were examined by Southern blot hybridization with pDP34 DNA probe, which recognizes X and Y chromosome-linked restriction fragment length polymorphisms (RFLPs). Contrary to the recent cytogenetic observations showing high incidence of loss of the Y chromosome in solid tumors, loss of the Y chromosome was observed in only 3 of 21 stomach cancers and 2 of 12 lung cancers. Gain of the Y chromosome was found in one of 12 lung cancers, but not in any of the stomach cancers. No X chromosome abnormality was found in any of these 33 stomach cancers and lung cancers.

Humans↗
PubMed1987

The complete primary structure of the rat A-raf cDNA coding region: conservation of the putative regulatory regions present in rat c-raf.

A-raf gene was first detected by low-stringent hybridization with v-raf and was reported as a possible oncogene. We have cloned rat A-raf cDNA and determined the complete nucleotide sequence over its long open reading frame. Alignment of rat A-raf- and c-raf-deduced amino acid sequences shows 59.4% homology. Both the ATP binding site and the kinase domain are conserved in A-raf as in c-raf. Furthermore, three regions highly conserved between A-raf and c-raf were identified in the 5'-half region of c-raf which has been shown to be deleted in the activated form of c-raf. These regions were speculated to be the candidates of the regulatory domain controlling the protein kinase activity of raf products. Southern blot analysis shows that genes homologous to A-raf and c-raf are present as independent loci in Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae and Candida boidinii. A-raf was expressed in several tissues and cell line at various amounts.

Amino Acid Sequence↗
PubMed1987

Recently identified nitrite-reactive compounds in food: occurrence and biological properties of the nitrosated products.

Various Japanese foodstuffs are directly-acting mutagens in Salmonella typhimurium TA100 after nitrite treatment. Such mutagen precursors include tyramine and beta-carboline derivatives, isolated from soya sauce, and indole-3-acetonitrile, 4-methoxyindole-3-acetonitrile and 4-methoxyindole-3-aldehyde, isolated from fresh Chinese cabbage. A mutagen produced from tyramine with nitrite was found to be 4-(2-aminoethyl)-6-diazo-2,4-cyclohexadienone (3-diazotyramine), and one produced from indole-3-acetonitrile with nitrite to be 1-nitrosoindole-3-acetonitrile. These two mutagens were directly-acting mutagens not only in S. typhimurium TA100 and TA98 but also in Chinese hamster lung cells, using diphtheria toxin resistance as a selective marker. The carcinogenicity of 3-diazotyramine was demonstrated in male Fischer 344 rats. Tyramine, beta-carboline and indole compounds are present ubiquitously in our environment, especially in foods. Therefore, the role of these newly identified mutagen precursors in the development of human cancer should be taken into consideration.

Acetonitriles↗
PubMed1987

Effect of cigarette smoking and dietary factors on the amount of N-nitrosothiazolidine 4-carboxylic acid and N-nitroso-2-methyl-thiazolidine 4-carboxylic acid in human urine.

The effects of cigarette smoking and dietary factors on urinary excretion of N-nitrosothiazolidine 4-carboxylic acid (NTCA; N-nitrosothioproline) and N-nitroso-2-methylthiazolidine 4-carboxylic acid (NMTCA; N-nitroso-2-methylthioproline) were studied in a male volunteer and in healthy Japanese subjects from the general population and Seventh-Day Adventists (SDA). Twenty-four-hour urine samples from the male volunteer were collected on 20 smoking days and 20 nonsmoking days during ingestion of a fixed diet, and the amounts of urinary N-nitrosamino acids were analysed by gas chromatography-thermal energy analysis. Cigarette smoking caused about two-fold (significant) increases in the amounts of NTCA and NMTCA in the volunteer. In the male subjects from the general population, not controlled for diet, the amounts of NTCA and NMTCA in 24-h urines of smokers were also significantly higher than those of the nonsmokers. The urinary excretions of NTCA and NMTCA in SDA were lower than those of nonsmokers in the general population. It was concluded that cigarette smoking is one of the important factors in determining the amounts of NTCA and NMTCA in human urine. Dietary factors also apparently influence the urinary levels of these N-nitrosamino acids. In addition, an apparent sex difference in the urinary excretion of NTCA and NMTCA (about two-fold higher in females) was observed in the general population but not in SDA. The N-nitrosoproline (NPRO) level was significantly higher in SDA than in nonsmokers in the general population.

Adult↗
PubMed1986

Establishment of a human pancreatic adenocarcinoma cell line (PSN-1) with amplifications of both c-myc and activated c-Ki-ras by a point mutation.

A human pancreatic cancer cell line, PSN-1, was established from pancreatic adenocarcinoma tissue that had been stored for 1.5 years at -80 degrees C without any special treatment. The stored tissues were first transplanted into nude mice, and from the xenograft, the PSN-1 cell line was established. The original primary tumor and two metastatic lymph nodes were previously found to have 50-fold amplification of c-myc and also 3- to 6-fold amplification of activated c-Ki-ras with a point mutation from GGT to CGT at codon 12. PSN-1 cells are unique in that amplifications of both c-myc and activated c-Ki-ras are present in the same degree as the original tumors. These cells were also found to contain increased amounts of c-myc and c-Ki-ras transcripts.

Adenocarcinoma↗
PubMed1986

Expression of the c-Ha-ras and c-myc genes in aflatoxin B1-induced hepatocellular carcinomas.

Expression and activation of several c-oncogenes in seven hepatocellular carcinomas from seven separate rats treated with aflatoxin B1 (AFB1) were examined by Northern and Southern blot analyses. Both c-Ha-ras and c-myc transcripts were elevated at high levels in all hepatomas. Moreover, in one of them, T2-1 hepatoma, the c-myc gene was amplified only in a tumor part of liver without significant rearrangement. N-ras specific transcripts were not elevated in these hepatomas. The present data suggest that the consistently increased expression or deregulation of the c-myc and c-Ha-ras genes may play an important role in the development of hepatomas induced by AFB1.

Aflatoxin B1↗
PubMed1986

Synergistic stimulation of histamine release from rat peritoneal mast cells by 12-O-tetradecanoylphorbol 13-acetate (TPA)-type and non-TPA-type tumor promoters.

Thapsigargin, a non-TPA (12-O-tetradecanoylphorbol 13-acetate)-type tumor promoter, provoked histamine release from rat peritoneal mast cells at concentrations above 30 ng/ml, but not at 10 ng/ml. TPA-type tumor promoters such as TPA, teleocidin and aplysiatoxin released very little, if any, histamine even at 100 ng/ml. When mast cells were incubated in medium containing thapsigargin at 10 ng/ml and varying concentrations of TPA-type tumor promoters, histamine release was increased synergistically. Maximum synergistic effects were observed at 10 ng/ml of each TPA-type tumor promoter. Palytoxin, another non-TPA-type tumor promoter, having no effect on histamine release at up to 10 pg/ml, also induced histamine release in the presence of 10 ng/ml of each TPA-type tumor promoter. However, no synergistic effect on histamine release was observed when mast cells were incubated in medium containing two different non-TPA-type tumor promoters, e.g., 10 ng/ml thapsigargin and 10 pg/ml palytoxin, or in medium containing two different TPA-type tumor promoters, e.g., TPA and teleocidin, TPA and aplysiatoxin, or teleocidin and aplysiatoxin (all at 10 ng/ml). These results suggest that the release of histamine from mast cells is stimulated synergistically under the mutual influence of TPA-type tumor promoters and non-TPA-type tumor promoters.

Animals↗
PubMed1986

Presence of human papillomavirus type-16 and type-18 DNA sequences and their expression in cervical cancers and cell lines from Japanese patients.

Southern blot analyses of surgical specimens of cervical carcinoma from Japanese patients showed that 3/9 samples contained human papillomavirus (HPV) type-16 DNA sequences, and 2 contained HPV type-18 DNA sequences. By Northern blot analyses, RNA transcripts of HPV DNA sequences were demonstrated in some of the tissues containing HPV type-16 or HPV type-18 DNA sequences. Two cell lines established from cervical cancers of Japanese patients also contained HPV type-18 genomes and these cell lines contained HPV type-18 transcripts. Two other cervical cancer cell lines from a Japanese patient were found to contain HPV type-16 DNA sequences and their RNA transcripts.

Adenocarcinoma↗
PubMed1986

Amplification of c-erbB-2 oncogene in human adenocarcinomas in vivo.

There are two genes related to the viral erbB gene in the human genome. c-erbB-1 is the same as the gene for the epithelial-growth-factor (EGF) receptor, and c-erbB-2 encodes a receptor-like protein very similar to, but distinct from, the EGF receptor. Hybridisation analysis of DNA from 101 fresh human malignant tumours showed that the c-erbB-2 gene was amplified in 5 of 63 adenocarcinomas and none of 38 other types of tumours, whereas the c-erbB-1/EGF-receptor gene was amplified only in 1 of 8 squamous-cell carcinomas. Thus, the protein products of the amplified c-erbB-2 gene may have a role in the evolution of adenocarcinomas, as does the EGF receptor in some squamous-cell carcinomas.

Adenocarcinoma↗
PubMed1986

L-isoleucine and L-leucine: tumor promoters of bladder cancer in rats.

A 4-week assay for screening tumor promoters of bladder cancer has been developed in which increased agglutinability of isolated rat bladder cells with concanavalin A is used as an indicator. On the basis of this assay system, L-isoleucine and L-leucine were suspected of being possible tumor promoters. Results of 40- to 60-week carcinogenesis experiments in which N-butyl-N-(4-hydroxybutyl)nitrosamine was used as an initiator demonstrate that L-isoleucine and L-leucine promote bladder cancer in rats. This finding may be relevant to the high incidence of human bladder cancer in Western countries, where the diet is rich in protein.

Animals↗
PubMed1986

Thapsigargin, a histamine secretagogue, is a non-12-O-tetradecanoylphorbol-13-acetate (TPA) type tumor promoter in two-stage mouse skin carcinogenesis.

Thapsigargin, a hexaoxygenated tetraacylated sesquiterpene lactone, induced irritation of mouse ear and histidine decarboxylase (HDC) activity in mouse skin, but it did not induce ornithine decarboxylase in mouse skin or adhesion of human promyelocytic leukemia (HL-60) cells. Although thapsigargin did not give consistent positive results in a short-term screening system for tumor promoters, it was tested in a two-stage carcinogenesis experiment on mouse skin. The potency of thapsigargin to induce HDC in mouse skin was used to determine the dose in this experiment. Application of 10 micrograms (17 nmol) thapsigargin induced HDC activity of 139 pmol CO2/mg protein per 60 min. Tumors were found in the skin of 53.5% of the mice treated with DMBA plus 5 micrograms (8.5 nmol) thapsigargin in week 22, in none of those treated with thapsigargin alone by week 30. One tumor appeared in 1 of 15 mice treated with DMBA alone in week 21. Thapsigargin cannot bind to the phorbol ester receptor in the particulate fraction of mouse skin and so is classified as a non-12-O-tetradecanoylphorbol-13-acetate (TPA) type tumor promoter. It is a new tumor promoter differing in many respects from the well-defined TPA type tumor promoters. Several naturally occurring analogues of thapsigargin, such as thapsigargicin and thapsitranstagin, might also be new non-TPA type tumor promoters, because thapsigargicin and thapsitranstagin induced irritation of mouse ear and HDC activity in mouse skin.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1986

Strain differences in mice with invasive bladder carcinomas induced by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Papillary superficial and nonpapillary invasive bladder carcinomas of humans are two disease entities exhibiting completely different biological behavior. Studies were performed on the susceptibilities of various strains of mice to induction of bladder carcinomas by N-butyl-N-(4-hydroxybutyl)nitrosamine (BHBN), and the type of carcinomas that developed. BHBN at concentrations of 0.05% and 0.01% in drinking water was given to female mice of strains A/Jax, AKR/Jax, C3H/He, DBA/2, and C57BL/6 for 22 weeks. The incidence of nonpapillary invasive bladder carcinomas in these strains was 40%, 100%, 100%, 89%, and 89%, respectively, in groups treated with 0.05% BHBN and 30%, 60%, 60%, 90%, and 40%, respectively, in groups treated with 0.01% BHBN. At both levels BHBN and in all strains the bladder carcinomas induced were of the nonpapillary invasive type.

Animals↗
PubMed1986

Mutagenicities of indole and 30 derivatives after nitrite treatment.

Indole and 7-derivatives, L- and D-tryptophan and 9 derivatives, and beta-carboline (norharman) and 11 derivatives were tested for mutagenicity to Salmonella typhimurium TA100 and TA98 after nitrite treatment. 1-Methylindole, which is present in cigarette smoke condensate (Grob and Voellmin, 1970; Hoffmann and Rathkamp, 1970), was the most mutagenic to TA100 without S9 mix after nitrite treatment, inducing 615,000 revertants/mg. 2-Methylindole, 1-methyl-DL-tryptophan, harmaline and (-)-(1S,3S)-1,2-dimethyl-1,2,3,4-tetrahydro-beta-carboline-3- carboxylic acid also showed strong mutagenicity after nitrite treatment, inducing 129,000, 184,000, 103,000 and 197,000 revertants/mg, respectively. These mutagenic potencies were comparable with those of benzo[alpha]pyrene, 3-methylcholanthrene and 2-amino-9H-pyrido[2,3-b]indole (A alpha C) (Sugimura, 1982). Of 31 compounds tested, 22 were mutagenic after nitrite treatment. Since various indole compounds are ubiquitous in our environment, especially in plants, the presence of their mutagenicities after nitrite treatment warrants further studies, including those on their in vivo carcinogenicities.

Alkaloids↗