Summary Unsaturated fatty acids, including n-3 polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (C225, DHA) and eicosapentaenoic acid (C20.5, EPA), and a series of n-6 PUFAs were investigated for their anti-tumour and antimetastatic effects in a subcutaneous (s.c.) implanted highly metastatic colon carcinoma 26 (Co 26Lu) model. EPA and DHA exerted significant inhibitory effects on tumour growth at the implantation site and significantly decreased the numbers of lung metastatic nodules. Oleic acid also significantly inhibited lung metastatic nodules. Treatment with arachidonic acid showed a tendency for reduction in colonization. However, treatment with high doses of fatty acids, especially linoleic acid, increased the numbers of lung metastatic nodules. DHA and EPA only inhibited lung colonizations when administered together with the tumour cells, suggesting that their incorporation is necessary for an influence to be exerted. Chromatography confirmed that contents of fatty acids in both tumour tissues and plasma were indeed affected by the treatments. Tumour cells pretreated with fatty acids in vivo, in particular DHA, also showed a low potential for lung colony formation when transferred to new hosts. Thus, DHA treatment exerted marked antimetastatic activity associated with pronounced change in the fatty acid component of tumour cells. The results indicate that uptake of DHA into tumour cells results in altered tumour cell membrane characteristics and a decreased ability to metastasize.Keywords: docosahexaenoic acid; unsaturated fatty acid; metastasis; colon carcinoma 26As tumour metastasis exerts an adverse influence on the prognosis of patients and is a major cause of cancer death, a considerable number of investigations into its biological, molecular and genetic features have been conducted (Raz and Ben-Ze'ev, 1987; Bertomeu et al, 1993). These investigations have indicated that tumour metastases are established by an inter-related sequence of processes, depending on various factors derived from both the tumour and the host. There is substantial evidence that the membrane properties of tumour cells play a major role in the interactions between themselves and the surrounding environment (Awad and Spector, 1976;Schroeder, 1984;Taraboletti et al, 1989;Dahiya et al, 1992). Studies on mice have revealed that plasma membranes of tumour sublines with high metastatic ability exhibit a more fluid state than those with low metastatic ability, based on differences in lipid composition and lipid-protein ratios (Kier and Franklin, 1991). Furthermore, studies have demonstrated that the chemical and physical properties of cell membranes are modified by both the amount and type of fat in the diet, and this influences growth and/or alters the metastatic ability of tumour cells (Chen et al, 1992;Rose and Hatala, 1994). Diets rich in linoleic acid have been found to enhance the growth and metastasis of transplantable mammary carcinomas in rodents (Rao and Abraham, 1976;. In a study of dietary n-3 PUFAs in a ...

Increasing attention is being paid to the possibility of applying cancer chemopreventive agents for individuals at high risk of neoplastic development. For this purpose by natural compounds have practical advantages with regard to availability, suitability for oral application, regulatory approval and mechanisms of action. Candidate substances such as phytochemicals present in foods and their derivatives have been identified by a combination of epidemiological and experimental studies. Plant constituents include vitamin derivatives, phenolic and flavonoid agents, organic sulfur compounds, isothiocyanates, curcumins, fatty acids and d-limonene. Examples of compounds from animals are unsaturated fatty acids and lactoferrin. Recent studies have indicated that mechanisms underlying chemopreventive potential may be combinations of anti-oxidant, anti-inflammatory, immune-enhancing, and anti-hormone effects, with modification of drug-metabolizing enzymes, influence on the cell cycle and cell differentiation, induction of apoptosis and suppression of proliferation and angiogenesis playing roles in the initiation and secondary modification stages of neoplastic development. Accordingly, natural agents are advantageous for application to humans because of their combined mild mechanism. Here we review naturally occurring compounds useful for cancer chemprevention based on in vivo studies with reference to their structures, sources and mechanisms of action.

Isoliquiritigenin (ILTG), a flavonoid group compound, exists in some foodstuffs and herbal medicines such as licorice (Glycyrrhiza uralensis Fisher). Previously, we showed that ILTG can suppress azoxymethane (AOM)-induced colon carcinogenesis in ddY mice. In the present report, we present evidence that ILTG markedly decreases both prostaglandin E 2 (PGE 2 ) and nitric oxide (NO) production in RAW264.7 mouse macrophage cells. The decrease of PGE 2 was dependent on cyclooxygenase-2 (COX-2) expression and the decrease of NO appeared due to a decrease in inducible nitric oxide synthase (iNOS) protein expression. In mouse and human colon carcinoma cells, ILTG treatment suppressed cell growth and caused apoptosis. soliquiritigenin (ILTG), a flavonoid with a chalcone structure ( Fig. 1), is reported to have vasorelaxant, 1) anti-platelet aggregation, 2) and anti-allergic activity.3) With regard to effects on carcinogenesis and related processes, ILTG has been shown to inhibit ornithine decarboxylase activity and to suppress 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis, 4) to reduce 32 P-incorporation into phospholipids of HeLa cells promoted by 12-O-tetradecanoyl-phorbol-13-acetate (TPA), 5) to inhibit growth of prostate cancer cell lines 6) and to decrease tube formation in vascular endothelial cells.7) Recently, it was reported that ILTG can stimulate apoptotic activity by inhibition of glucose transmembrane transport and promotion of Bax expression in mouse melanoma cells. 8) We previously found that ILTG markedly inhibited induction of aberrant crypt foci (ACF) and colon carcinoma development in azoxymethane (AOM)-treated ddY mice. 9) To clarify the inhibition mechanisms, we conducted the present examination of the effects of ILTG on cyclooxygenase (COX) and inducible nitric oxide synthase (iNOS)-related parameters considered relevant to colon carcinogenesis 10, 11) using the RAW264.7 mouse macrophage cell line, in which COX and iNOS are induced by LPS stimulation. Furthermore, the effects of cell proliferation and induction of apoptosis in three colon cancer cell lines were examined. In order to determine whether ILTG is actually effective as a chemopreventer in other species, we also conducted an in vivo study in rats with putatively preneoplastic ACF lesions as the end-point. Materials and MethodsChemicals. ILTG was synthesized at the Department of Natural Medicine and Phytochemistry, Meiji Pharmaceutical University, Tokyo (Fig. 1). AOM, 5-fluorouracil (5-FU) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were purchased from Sigma Chemical Co (St. Louis, MO). Lipopolysaccharide (LPS) was purchased from Difco Labs (Detroit, MI). Propidium iodide was purchased from Nacalai Tesque (Kyoto).Cell culture. Mouse macrophage RAW264.7 cells, and RCN-9, rat colon cancer cells, were provided by the RIKEN Cell Bank (RCB) (Ibaraki). COLO-320DM, human colon cancer cells, were kindly provided by Ms. Mari Onozuka (Kyoto Prefectural University of Medicine, Kyoto). The Colon 26 line, mo...

Platinum complexes derived from three isomers of 1,2-diaminocyclohexane have been synthesized and their antitumor activities were evaluated against ascites Sarcoma-180. All the platinum complexes had high antitumor activity. Platinum complexes derived from cis-1,2-diaminocyclohexane were more effective than those derived from trans-l-and trans-d-1,2-diaminocyclohexane. Among the platinum complexes tested, oxalato(cis-1,2-diminocyclohexane)platinum had a remarkably high therapeutic index. Modification of the nonleaving group as well as that of the leaving group is important in order to find better antitumor platinum complexes.

The effects of oral administration of bovine lactoferrin (bLF) and its hydrolysate on the lung colonization by colon 26 carcinoma were investigated. At doses of 100 or 300 mg/kg/day for seven successive days, bLFs demonstrated a significant inhibitory effect on experimental metastasis, which indicated effectiveness before and after tumor implantation. Oral administration of bLFs augmented CD4+, CD8+, and asialoGM1+ cells in the spleen and peripheral blood. Their cytotoxic activities against Yac-1 and colon 26 carcinoma were enhanced by bLF. In the small intestinal epithelium, CD4+ and CD8+ cells were markedly increased, and, simultaneously, enhanced production of interleukin-18 (IL-18) was confirmed in the intestinal epithelial cells. In this model, intravenous injection of murine IL-18 showed significant inhibition of the lung colonization by colon 26 carcinoma. These results suggested that inhibition of experimental metastasis by oral administration of bLF and pepsin hydrolysate of bLF might be due to enhanced cellular immunity, presumably mediated by enhanced IL-18 production in the intestinal epithelium.