3. Chemotherapy Division

Generation of Human Proto c-Ha-ras Transgenic Rats and Investigation of Susceptibility to Chemical Carcinogens Transgenic mice transfected with the human c-Ha-ras protooncogene have been shown to be particularly susceptible to a number of carcinogens. However, there are limitations as to which organs can be appropriately investigated in these mice. To overcome this problem, the production of trans-genic rats carrying the human c-Ha-ras protooncogene is presently underway.

Genetic Alterations in Bladder Carcinogenesis

Aberrant expression of p16 mRNA was found in both human and murine bladder carcinomas. To identify the genes involved in bladder carcinogen-esis, mRNA differential display techniques were applied. Thirteen clones were found to be specifically expressed in non-tumorigenic rat urinary bladder cell lines. One clone was found to be the rat homologue of the human maspin gene, a candidate breast cancer suppressor gene. Normal human and rat bladder epithelial cells demonstrated immunohistochemical staining for maspin protein indicating that its inactivation may be involved in human and rat bladder carcinogenesis. A full length cDNA, obtained by the 5' RACE method, was transfected into a bladder carcinoma cell line. The resulting obvious reduction in tumorigenicity in nude mice demonstrated that this small proline rich protein homologue indeed has tumor suppressing activity.

Study of Chemopreventive Agents Against Carcinogenesis

Previously, the promoting potentials of swine-serum-induced liver fibrosis and tamoxifen and the inhibiting influences of plant antioxidants and ascorbic acid derivatives on hepatocarcinogenesis were examined.(38-41) Decreased expression of connexin 32 in clofibrate-induced lesions was reported, as well as organotropic effects and suppression of colon tumors by polyunsaturated fatty acids.(42,43) More recently, the chemopreventive influences of bovine lactoferrin (bLF) and related compounds on colon carcinogenesis were investigated in male F344 rats initially treated with azoxymethane. Significant reductions in both the incidence and the number of adenocarcinomas of the large intestine were observed with almost all treatments for 36 weeks, with no toxicity being noted. The plant carotenoids, lycopene, fucoxanthin, lutein and curcumin as well as a derivative, tetrahydrocurcumin, were also examined for their inhibitory effects on colon carcinogenesis when given to mice after induction of tumor growth with dimethylhydrazine. Fucoxanthin, lutein and tetrahydrocurcumin significantly reduce the development of preneo-plastic aberrant crypt foci in the mouse colon after dimethylhydrazine initiation.

Inhibitory Effects of Docosahexaenoic Acid (DHA) on Lung Metastasis of Colon Carcinoma 26 Cells

Various unsaturated fatty acids, including DHA and EPA, were investigated for their antimetastatic effects on s.c. implanted colon carcinoma 26 cells possessing high metastatic potential to the lung. Oleic acid, EPA and DHA significantly decreased and linoleic acid increased the numbers of metastatic lung nodules formed. Chromatography confirmed the fatty acid contents of both tumor tissues and plasma to be significantly affected by the treatments. Tumor cells pretreated with fatty acids in vivo, particularly DHA, also showed low metastatic potential, associated with a pronounced change in their fatty acid composition. The results indicate that uptake of DHA into tumor cells results in altered tumor cell membrane characteristics and a decreased ability to metastasize.

Tumor-regressing Factor: As a Novel Factor Related to Complement Component C3

A potent tumor-regressing factor (TRF) with chemotactic activity for neutrophils was found in the serum of mice bearing tumors undergoing rapid regression caused by antitumor polysaccharides. The factor was purified as a giant molecule with a molecular weight of several to 10 million daltons, composed mainly of disulfide-linked 66-Kd monomers. The NH2-terminal amino acid sequence was found to be identical to the b chain of complement component C3. However, the monomer did not recognize an antibody against C3b or inhibit the chemotactic activity of TRF. Results for the biological, immunological and chemical characteristics of TRF thus suggest it is structurally related to, but essentially different from, C3 and C3b.

Attenuation of AGT Activity in Cell Lines

To facilitate understanding of the mechanism of action of 6-aryl-2,4-diamino-1,3,5-triazines, the modulating effects of this compound on cisplatin cytotoxicity against a human cancer cell line were investigated in vitro. Attenuation of CDDP cytotoxicity, observed in the presence of diaminotriazine at 100 uM, was demonstrated to be due to potentiation of AGT activity in KATO III cells.

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