Cheol Beom Park

Soluble and insoluble fiber influences on cancer development.

2. Epidemiological and experimental evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 2.1. Colon cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 2.2. Breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 2.3. Endometrial cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

A ferulic acid derivative, ethyl 3-(4'-geranyloxy-3-methoxyphenyl)-2-propenoate, as a new candidate chemopreventive agent for colon carcinogenesis in the rat.

The inhibitory influence of ferulic acid (FA), a rice germ component, and its geranylated derivative 3‐(4′‐geranyloxy‐3‐methoxyphenyl)‐2‐propenoate (EGMP) on the post‐initiation stage of azoxy‐methane (AOM)‐induced colon carcinogenesis was studied in male F344 rats given two s.c. injections of AOM (15 mg/kg body weight) during week 1. Diets containing EGMP or FA at doses of 0.1 or 0.2% were then fed for 3 weeks from week 2 to 5, when the animals were sacrificed. The numbers of aberrant crypt foci (ACF) and aberrant crypts (AC) per rat in the group given 0.2% FA were significantly decreased (P<0.001) as compared to the AOM alone group. Furthermore, the numbers of ACF and AC per rat fed the 0.2% and 0.1% EGMP were significantly reduced (P<0.001 and P<0.01, respectively). Colonic epithelial cells in S‐phase, as measured by bromodeoxy‐uridine (BrdU) labeling, in rats fed EGMP were significantly decreased in the 0.2 and 0.1% EGMP groups as compared to the AOM alone group (P<0.05). BrdU labeling indices in rats fed FA and EGMP assessed by a test using a coefficient for linear contrast were also significantly decreased as compared to the AOM alone value (P<0.05, P<0.01, respectively). The results indicate that FA and EGMP have inhibitory effects on ACF and AC development, EGMP being more potent, possibly due to stronger suppressive effects on cell proliferation. No toxic effects were observed in rats given either compound in terms of body and organ weights, and liver or kidney histology. The findings thus suggest that EGMP and FA, especially the former, might have potential as chemopreventive agents against colon tumor development.

Physical exercise: a pillar for cancer prevention?

Both epidemiological and experimental studies have shown that physical exercise deserves particular attention in any consideration of approaches to the prevention of neoplasia, especially since it also exerts consistent beneficial effects on the other major chronic diseases prevalent in the Western world, atherosclerosis and non-insulin dependent diabetes mellitus (NIDDM). The organ sites for which strong evidence has been gained for a protective influence of exercise or an elevated risk with a sedentary existence include the colon, prostate, breast and endometrium. The underlying mechanisms appear to centre on the hormones insulin and oestrogen, serum elevation of both of these endocrine factors being associated with increased risk of neoplastic development. The immense potential benefit of an increased level of exercise in the general population suggests that commensurate measures should be taken in the field of cancer education.

Organotropic chemopreventive effects of n-3 unsaturated fatty acids in a rat multi-organ carcinogenesis model

Organotropic chemopreventive effects of n‐3 unsaturated fatty acids were studied using a multi‐organ carcinogenesis model in male rats. Rats were treated with diethylnitrosamine (DEN), N‐methyl‐N‐nitrosourea (MNU), N‐butyl‐N‐4‐hydroxybutylnitrosamine (BBN), 1,2‐dimethylhydrazine (DMH) and dihydroxy‐di‐n‐propylnitrosamine (DHPN) during the first 7 weeks, and then given unsaturated fatty acid (UFAs), docosahexaenoic acid (n‐3, C22:6) (DHA), eicosapentaenoic acid (n‐3, C20:5) (EPA), linoleic acid (n‐6, C18:2) (LA) or oleic acid (n‐9, C18:1) (OA) at a dose of 1.0 ml/rat, 3 tunes a week by gavage for the consecutive 30 weeks. All rats were fed a low LA basal diet throughout the experiment and a calorie‐restricted basal diet during the period of UFAs feeding administration. DHA significantly reduced tumor size and numbers in the large intestine as compared to OA treatment. Furthermore, DHA showed a tendency to inhibit carcinogenesis in the small intestine and lung. EPA also showed a tendency to inhibit intestinal carcinogenesis. On the other hand, LA showed a tendency to inhibit lung carcinogenesis, but to promote large intestinal carcinogenesis. However these UFAs did not influence preneoplastic and neoplastic lesion development in the liver, kidney, and urinary bladder. Levels of the administered fatty acids were clearly increased in the serum and organs. In contrast, arachidonic acid (AA) levels in the large and small intestines and liver were markedly decreased by treatment with DHA and EPA. Decreased levels of AA in the large intestine correlated well with tumor incidence, although the number of glutathione S‐transferase‐positive (GST‐P+) foci showed an inverse correlation with AA levels. The data thus provide evidence that an organotropism exists with regard to the influence of UFAs on carcinogenesis, which correlates with reduction of tissue AA levels in the target organs.

Rapid induction of skin and mammary tumors in human c‐Ha‐ras proto‐oncogene transgenic rats by treatment with 7,12‐dimethylbenz[a]anthracene followed by 12‐O‐tetradecanoylphorbol 13‐acetate

We have established a transgenic rat line carrying 3 copies of the human c‐Ha‐ras proto‐oncogene with its own promoter region (Jcl/SD‐TgN(HrasGen)128Ncc) (Hras128 rat), expression being detectable in almost all organs. We have already demonstrated that the rat is highly sensitive to mammary, esophagus and bladder carcinogenesis. In the present study, male and female transgenic and wild‐type littermates were topically treated with 2.5 mg of 7,12‐dimethylbenz[a]anthracene (DMBA) dissolved in 1.0 ml of acetone on the back skin at 50 days after birth. Starting 1 week thereafter, they were again topically treated with 100 nmol of 12‐O‐tetradecanoylphorbol 13‐acetate (TPA) dissolved in 0.5 ml of acetone 3 times weekly for the following 31 weeks. In males treated with DMBA and/or TPA, skin tumors, including both squamous cell papillomas (SCP) and carcinomas (SCC), were preferentially induced at the DMBA‐TPA painting sites: DMBA‐TPA, 15/15 (100%); DMBA, 6/8 (75%); TPA, 1/6 (16.7%). They were also, unexpectedly, induced on remote scrotal skin: DMBA‐TPA, 13/15 (86.7%); DMBA, 5/8 (62.5%); TPA, 0/6 (0%). Lesions were thus more frequent in the DMBA‐TPA group than with DMBA or TPA alone. In females, adenomas and adenocarcinomas of the mammary glands were preferentially induced: DMBA‐TPA, 12/14 (85.7%); DMBA, 6/8 (75%); TPA, 3/6 (50%), with only a few small skin papillomas at painting sites. Incidences and numbers of the mammary and skin tumors were much greater in Hras128 rats than in their wild‐type counterparts. PCR‐RFLP analysis of the transgene indicated that the percentage of the cell populations harboring a mutation in codons 12 and/or 61 ranged from 2% to 60% in individual tumors; skin tumors showed more mutations in codon 61 in the DMBA‐treated groups. In contrast, no mutations were detected in the endogenous rat c‐Ha‐ras gene. These results indicate that the Hras128 rat is highly susceptible to DMBA‐TPA skin and mammary carcinogenesis, thus providing a unique painting model for skin as well as mammary gland carcinogenesis, that would be suitable for investigating the role of transgene mutations.

European country comparisons provide evidence of a link between colon cancer and adenocarcinoma development in the lung but not the oesophagus

Relative incidence rates of lung cancers demonstrate marked international variation in values for the different histological sub-types. In order to determine whether adenocarcinomas (ACs) in this site might share risk factors with other ACs, for example, in the breast, prostate, oesophagus and colon, a comparison of data in the IARC/WHO Cancer Incidence in Five Continents (Volume VII) was made for selected registries in Europe. Significant correlations were found between lung AC incidences/100,000 population and prostate and colon cancers in males (P < 0.005 and P < 0.05, respectively) and for breast and colon in females (P < 0.05 for both). Partial correlation coefficients were significant for lung and colon (P < 0.001) and prostate and colon (P < 0.005) in men, and for breast and colon in women (P < 0.005). A significant negative correlation with prostate cancer was noted for lung ACs in men. The results provide support for shared risk factors between lung Acs and colon cancers but do not indicate any link with AC development in the oesophagus. Data from registries in the UK and Italy were remarkable for high incidences of oesophageal and lung ACs, respectively, pointing to major differences in environmental risk factor or beneficial influence acting on these sites between the two countries.

Cross-country comparisons suggest shared risk factors for carcinomas, including male lung adenocarcinoma and colon cancer development

Smoking is clearly the major risk factor for both squamous cell carcinomas (SCCs) and adenocarcinomas (ACs) of the lung, although less so for the latter, where other influences appear to be important. In order to determine whether cross-country comparisons might provide evidence of shared risk factors with cancers in other organs of males, an examination of IARC/WHO data for cancer incidence was made for countries/registries in Europe, North America, Australia and Asia. Significant simple correlations, which persisted on partial analysis, were observed between lung SCCs and tumors of the larynx (P < 0.001), but not the buccal cavity or oesophagus, along with a link to rectal ACs (P < 0.001). Incidences of lung ACs also correlated with those for colon ACs (P < 0.001) but not lung SCCs. Oesophageal ACs were only related to colon cancers at the simple correlation level, this not persisting on partial analysis or separation into Asian and Western groups. The results suggest that blood borne factors, like hormones, may be important as determinants for the increasingly prevalent lung AC.

European registry comparisons provide evidence of shared risk factors for renal, colon and gallbladder cancer development.

In order to assess links between renal cell cancer (RCCs) and transitional cell cancers (TCCs) of the kidney and cancer development in other organs of the abdominal cavity, incidence data from the Cancer Incidence in Five Continents (Vol VII) were compared between various cancer registries in Europe. Significant correlations which persisted on partial analysis were observed between RCCs and carcinomas of the colon and gallbladder, as well as between the latter themselves. Kidney TCCs, in contrast, were associated with tumours of the urinary bladder. In addition, significant correlations between hepatocellular, but not cholangiocellular carcinomas, and gallbladder and colon cancers were observed. Data for pancreas and gallbladder neoplasms also correlated. Prostate cancer incidences, while positively linked to RCCs, negatively correlated with gallbladder rates. The results point to shared risk factors for RCCs and adenocarcinomas in a number of organs, suggesting a role for humoral agents. The present findings also underline the necessity of distinguishing between tumour types within organs in epidemiological investigations of causal influences.

Cross-country comparisons of colon and rectal cancer mortality suggest the existence of differences in risk factors in eastern and western Europe.

A comparison of relative mortality rates from colon and rectal cancers in World Health Organization data for various countries in Europe was undertaken to determine whether the two sites demonstrate a direct link. A significant correlation between figures for colon and rectal cancers was found throughout Europe but limited to males and only at the p < 0.05 level. Cluster analysis revealed marked differences between countries of the former west and east European blocks, the latter having much higher values for rectal cancers. Separation of countries on this basis gave rise to significant correlation between the two sites for both sexes (p < 0.05 and p < 0.001, respectively, for western and eastern males; and p < 0.05 and p < 0.001 for females). In order to assess the possible contribution of factors associated with squamous cell cancers (SCCs), data for buccal and cervical cancers, both more prevalent in eastern than in western Europe, were also compared. Whereas a significant correlation was evident between female rectal and cervical cancers overall and in the western countries (p < 0.05) this was not the case for the eastern countries. The results suggest that the observed excess of rectal cancer mortality in eastern European countries may not be simply due to factors contributing to SCCs, but that country level comparisons of individual harmful and beneficial influences, alone and in combination, might allow the underlying reasons to be explained.