3. Experimental Pathology and Chemotherapy Division
Susceptibility to chemical carcino-genesis of human c-Ha-ras Proto-oncogene Transgenic Rats
A rat line carrying three copies of the human c-Ha-ras proto-oncogene, including its own promoter region, was established. Expression of the transgene mRNA was detected in all organs. PCR-RFLP analysis and direct sequencing of the transgene indicated that most tumors induced by MNU contained cells with mutations at codon 12. However, the densities of the mutated bands and subsequent subcloning and sequencing revealed the presence of mixed populations of mutated and non-mutated cells, the latter being in the majority. By PCR-SSCP analysis, no mutations in codons 12 and 61 of rat endogenous c-Ha-ras gene were detected. These results indicate that rats carrying a human c-Ha-ras proto-oncogene are highly susceptible to mammary carcinogenesis and that this is not primarily due to mutations of the transgene or endogenous c-Ha-ras gene. The transgenic rats were also found to be highly susceptible to NMBA-induced esophagus carcinogenesis. Regardless of the mechanism involved, the human c-Ha-ras proto-oncogene transgenic rat could be utilized for the short-term detection of carcinogens and promoting agents active in the mammary gland.
Chemopreventive Effects of Dietary Factors on Tumor Development
Food-derived factors, like lactoferrin (bLF) that is a glycoprotein in milk, tetrahydrocurcumin (THC) that is a metabolite of curcumin in the intestines and serum, and 3-ethyl(4-geranyloxy-3-methoxyphenyl)-2-propionate (EGMP) that is a chemical derivative of ferulic acid in rice bran, have been shown to be promising chemopreventive agents. For example, bLF,(49) THC(50) and EGMP significantly inhibited azoxymethane (AOM)-induced rat and APCMin mouse intestinal carcinogenesis, possibly through supression of cell proliferation.(51)
To cast light on the role of insulin in neoplastic development and determine whether dehydroepiandrosterone (DHEA) might exert inhibitory effects, a series of reviews(52-56) and experiments,(57) were performed. The results suggest that insulin acts as a tumor promoter in the colon(58-60), while DHEA protects in the liver.
Promoting Effect of Caffeine on PhIP Colon Carcinogenesis
The effects of concurrent caffeine administration on the PhIP carcinogenicity were assessed. Caffeine significantly increased levels of CYP1A2. Combined administration of caffeine and PhIP resulted in a significant increase in colon aberrant crypt foci (ACFs) and CYP1A2 expression.
Inhibitory Effects of Bovine Lactoferrin on Colon Carcinoma 26 Lung Metastasis
Orally administered bLF significantly inhibited lung metastasis from s.c. implanted Co26Lu. AsialoGM1+ and CD8+ cells in white blood cells (WBC) were increased after bLF treatment. In vitro, the viability of Co 26Lu cells was markedly decreased when co-cultured with WBC from mice received bLF, but recovered by anti-asialoGM1 Ab or anti-CD8 mAb treatment. The results suggest bLF might find application for the control of metastasis.
Mechanisms and Histogenesis of carcinogenesis and Models for Environmental Carcinogen Assay
The role of abrogation of gap junction and overexpression of p16 gene in experimental urinary bladder carcinogenesis was analyzed.(61,62) Histogenesis of phenotypically different rat kidney tumors was clarified in a stereoscopic reconstruction study.(63)
Tumor-regressing Factor: a Novel Factor Related to but Different from Complement Component C3
Polysaccharide-induced tumor-regressing factor (TRF) is composed of a 70-kD monomer. The NH2-terminal amino acid sequence was identical to the b chain of complement C3. cDNAs from polysaccharide-treated mouse neutrophils which have 5ﾕ-terminal sequence identical to that of C3b chain were analyzed by 3ﾕ-RACE PCR. Two of them were shown to have unique sequences of 130-355 bp length at their 3' terminal ends.
Anti-angiogenic Activity of Diaminotriazines
Among triazine derivatives 4PyDAT had the highest inhibition of production of uPA in HT-1080 cells. This compound also demonstrated anti-angiogenic-activity in CAM assay and showed antitumor effect on HT-1080 and HT-29 solid tumors. The triazine did not show any toxicity against tumor cells or the hosts. Thus, non-toxic anti-angiogenic compounds of this type may be promising candidate antitumor agents.