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Biomedical subjects

Hiroyuki Tsuda

Publications and source records attributed to Hiroyuki Tsuda.

At least 55 records · Page 3Linked to original sources
PubMed2002

Down-regulation of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)-induced CYP1A2 expression is associated with bovine lactoferrin inhibition of MeIQx-induced liver and colon carcinogenesis in rats.

The inhibitory influence of bovine lactoferrin (bLF) on induction of preneoplastic hepatic glutathione S-transferase placental form-positive (GST-P( +)) cell foci and colon aberrant crypt foci (ACF) by diethylnitrosamine (DEN) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was investigated in F344 rats. Rats were initially treated with DEN, then placed on basal diet containing MeIQx (200 ppm) alone, MeIQx plus 2% bLF, or MeIQx plus 0.2% bLF from week 2 to week 8, with partial hepatectomy performed at week 3. Concomitant administration of 2% or 0.2% bLF with MeIQx caused significant dose-dependent decreases in both number and unit area of GST-P(+) cell foci (2% bLF, P < 0.001; 0.2% bLF, P < 0.01). Similar results were observed for MeIQx-induced colon ACF in the groups without DEN treatment (2% and 0.2% bLF, P < 0.05). To investigate the underlying mechanisms, we analyzed the influence of bLF on levels of cytochrome P4501A2 (CYP1A2), a metabolically activating enzyme of MeIQx in the liver. The results demonstrated that combined administration of 2% bLF significantly reduced levels of MeIQx-induced CYP1A2 mRNA (P < 0.05) and protein (P < 0.05) to the normal levels, in association with reduced values for MeIQx-DNA adducts (P < 0.05), liver GST-P(+) cell foci and colon ACF. These results suggest that bLF is a chemopreventive agent for DEN alone or DEN plus MeIQx-induced liver, and MeIQx-induced colon carcinogenesis in rats. One possible mechanism is a normalizing down-regulation of CYP1A2 expression by bLF, with consequent reduction of carcinogen activation and adduct formation.

Animals↗
PubMed2002

Transgenic rats carrying human c-Ha-ras proto-oncogene are highly susceptible to N-nitrosomethylbenzylamine induction of esophageal tumorigenesis.

A transgenic rat line carrying three copies of the human c-Ha-ras proto-oncogene, including its own promoter region, has been established in our laboratory (Hras128 rats), and shown to be highly susceptible to induction of mammary and urinary bladder tumors. Mutation analysis of induced lesions indicated the majority to contain some but not all cells with transgene mutation. In the present study, the susceptibility of Hras128 rats to N-nitrosomethylbenzylamine (NMBA) induction of esophageal tumors was examined with a similar mutation analysis of the transgenes. Male 6-week-old Hras128 and wild littermate rats were treated with NMBA, 0.5 mg / kg subcutaneously, 3 times a week for 5 weeks and then maintained for 5 weeks without any further treatment. Multiple esophageal tumors, squamous cell papillomas and carcinomas, rapidly developed within this 10-week experimental period in Hras128 rats (11.05 +/- 7.83 / rat). In contrast, wild-type littermates had only small numbers of mostly benign tumors (1.67 +/- 2.06 / rat). The Hras128 rats had no other tumors or abnormalities. In their esophageal lesions, codon 12 GGC to GAC mutations of the transgene were frequently detected by restriction fragment length polymorphisms (RFLP) and subsequent direct sequencing analysis (19 / 25, 76%). In the endogenous rat c-Ha-ras gene they were less frequent (2 / 25, 8%), than in wild-type rats (8 / 14, 57.1%). The densities of mutated bands in the RFLP analysis indicated that mutated cells were major populations in tumors, in contrast to the case with mammary and urinary bladder lesions. Furthermore, activated ras protein, detected by binding to raf protein, was clearly increased in tumors as compared to surrounding epithelium or the normal esophagus of untreated rats. The results show that Hras128 rats are highly susceptible to NMBA esophageal carcinogenesis, as well as induction of mammary and urinary bladder tumors, but that tissue-specific characteristics exist for the roles of transgene ras mutations.

Animals↗
PubMed2002

Cancer prevention by bovine lactoferrin and underlying mechanisms--a review of experimental and clinical studies.

In experimental studies, bovine lactoferrin (bLF) has been found to significantly inhibit colon, esophagus, lung, and bladder carcinogenesis in rats when administered orally in the post-initiation stage. Furthermore, concomitant administration with carcinogens resulted in inhibition of colon carcinogenesis, possibly by suppression of phase I enzymes, such as cytochrome P450 1A2 (CYP1A2), which is preferentially induced by carcinogenic heterocyclic amines. Enhancement of the activities of their phase II counterparts, such as glutathione S-transferase might have also played a critical role in post-initiation suppression in a study of tongue carcinogenesis. Anti-metastatic effects were moreover detected when bLF was given intragastrically to mice bearing highly metastatic colon carcinoma 26 cells (Co 26Lu), with apparent enhancing influence on local and systemic immunity. Marked increase in the number of cytotoxic T and NK cells in the mucosal layer of the small intestine and peripheral blood cells was thus found, this in turn enhancing the production of Interleukin 18 (IL-18) and caspase-1 in the epithelial cells of the small intestine, with possible consequent induction of interferon (IFN)-gamma positive cells. Furthermore, bLF has been found to exert anti-hepatitis C virus (HCV) activity in a preliminary clinical trial in patients with chronic active hepatitis due to this virus, a main causative factor in hepatocellular carcinoma development in Japanese. More extensive clinical trials are now underway in the National Cancer Center Hospital and other institutes to further explore the preventive potential against colon carcinogenesis.

Animals↗
PubMed2002

Food and Play Preferences - Does Cancer Prevention Require Targeting the Child?

Food preferences and habits regarding physical exercise and play regimens appear to become set relatively early in life, the mother being the major influence at this stage. Subsequently, the peer group takes on increasing importance, with continued roles for teachers and parents in providing an environment and guidance leading to adoption of a healthy or an unhealthy lifestyle. Since so many of the decisions that will determine exposure to risk and beneficial factors hinge on experience up to and through adolescence, the question arises as to whether more cancer prevention efforts should be directed at children and youths.

Editorial↗
PubMed2002

Smoking-Related Research in the Asian-Pacific Countries.

In addition to the obvious link between tobacco consumption and cancer of the lung and oral cavity, there is increasing evidence that carcinogens in smoke many also have an impact in many other organ sites. The potential damage of second hand smoke, especially to children, also requires stress. While studies of gene polymorphisms for enzymes involved in carcinogen metabolism have pointed to a genetic background to smoking likelihood and clearly increased risk of cancer development in many organs for smokers with decreased detoxification potential, the question of how to make best use of this information for practical prevention remains largely unexplored. Similarly, the fact of peer group and family influence in determining initiation of adolescent smoking has yet to be translated into a concrete strategy based on psychological understanding. Cessation programs for adult smokers on the other hand could make use of positive results from interventions in hospital settings, possibly married to screening programs for early cancers. Political and socioeconomic questions are clearly very important and putting into action principles of tobacco control efforts with collaboration between all of the interested parties must now be stressed. Government can play a very positive role by control of sales and marketing, heavy taxation and smoking bans, and provision of funding for research and community interventions, while education and awareness are natural targets of NGOs. The academic research community can perhaps best contribute by further clarifying mechanisms underlying tobacco-related disease, possibly with an emphasis on chemoprevention in association with epidemiological assessment of confounding factors, and also very importantly the psychosociology of the tobacco habit.

Journal Article↗
PubMed2002

Use of Wild Rodents for Environmental Monitoring - Comparison of Rats in Bangkok and Rural Areas of Thailand.

There is a great deal of concern regarding the hazard potential of human exposure to toxic substances and carcinogens as well as infectious agents in the environment. For monitoring purposes fish are well established with regard to aquatic pollution. However, for the human environment, mammalian species might be considered more relevant. As the various types of rats are one of the most common animals sharing human habitants they are natural candidates. In the present study, numbers of such wild rats were trapped in the metropolis of Bangkok and country regions of Thailand for comparison of lesions in the liver and lung which might provide indicators of carcinogens or other hazardous agents in the environment. Glutathione S transferase P form positive foci could be detected in livers, comparable to the laboratory rat case, but without any significant link to site of capture. In contrast, fatty liver and inflammation/cirrhosis were significantly more frequent in animals from the metropolis. Parasite infection also tended to be more prevalent, along with leptospirosis. Inflammatory change was similarly found in the lungs but without any variation between the city and countryside groups. These results suggest that wild rats could be employed as monitors of environmental agents of toxicological significance.

Journal Article↗
PubMed2002

Cancer Screening: A Review with Particular Attention to Areas for Future International Research Efforts.

For almost all of the sites of most common cancers, particularly the lung, colo-rectum and cervix, relatively inexpensive and reliable tests have been available for some time. Advances in imaging techniques now allow identification of early tumours in many other organs, including those that are normally associated with a very poor prognosis. In addition, increasing knowledge of the risk factors for cancer development in different organs imply more effective screening for early malignancies in high risk populations and the associated increase in the predictive value should mean that early intervention will result in a marked decrease in the mortality and morbidity due to a wide range of major cancers. However, there are many difficulties which remain to be overcome, especially in the psychosocial area. Problems with overdiagnosis and distinction of lesions most likely to actually give rise to cancers also require especial attention for the full promise of screening to be realised. In addition, choice of the most appropriate approach will require an in depth understanding of cultural factors impacting on screening behaviour and it is of paramount importance that both physicians and the public at large be fully aware of pitfalls and potential benefits. Thus research needs to be concentrated on effective education approaches as well as how to increase practical sensitivity and specificity of individual tests and determine the best follow-up for individuals testing positive.

Journal Article↗
PubMed2000

Milk Components as Cancer Chemopreventive Agents.

Since milk and dairy products constitute very important ingredients of the western style diet, a large number of epidemiological studies have been conducted to determine effects of their consumption on neoplastic development. However, reflecting the variety of included components, the data are to some extent equivocal. It has been proposed that whereas fats in general might promote tumour development, individual milk fats like conjugated linoleic acid and glycosh\ingolipids could exert inhibitory effects. There is also considerable evidence that calcium in milk products protects against colon cancer, while promoting in the prostate through suppression of circulating levels of 1,25 dihydroxyvitamin D. Whey protein may also be beneficial, as shown by both animal and human studies, and experimental data have demonstrated that the major component bovine lactoferrin (bLF), inhibits colon carcinogenesis in the post-initiation stage in male F344 rats treated with azoxymethane (AOM) without any overt toxicity. Results in other animal models have provided further indications that bovine lactoferrin might find application as a natural ingredient of milk with potential for chemoprevention of colon and other cancers.

Journal Article↗
PubMed2000

Promotion of Liver Lesion Development in the Syrian Hamster by Dietary Fat Following Multi-organ Initiation is Inhibited by DHEA-S Administration.

The influence of dietary supplementation with dehydroepiandrosterone-sulphate (DHEA-S) at 0.6% was investigated in male Syrian golden hamsters initiated by treatments with azoxymethane(AOM), and dihydroxy-di-n-propyl nitrosamine (DHPN), timed after transfer from a choline-deficient to a normal diet. These carcinogens respectively target the colon, and the respiratory tract, the liver and pancreas. A total of 75 animals were divided into 6 groups, 1-3 (20 animals each) receiving the initiation protocol of during the first 8 weeks, and 4-6 (5 animals each) given the vehicles alone. The hamsters in groups 2,3 and 5,6 then received a high fat diet (20% corn oil) while DHEA-S was given in addition for 20 weeks to groups 3 and 6. Groups 1 and 4 served as controls on the basal diet. Assessment of development of preneoplastic and neoplastic lesions, after sacrifice at week 28, revealed increase in hepatocellular liver nodules and the index of BrdU incorporation in the hepatocellular cells of the liver in the initiated animals given the high fat diet. This was significantly reduced by the DHEA-S supplementation. Non-significant tendencies for high fat enhancement and hormone protection were also observed for lung and colon tumors.

Journal Article↗
PubMedDate not supplied

Value of GST-P positive preneoplastic hepatic foci in dose-response studies of hepatocarcinogenesis: evidence for practical thresholds with both genotoxic and nongenotoxic carcinogens. A review of recent work.

Recent low-dose carcinogenesis studies, including major group projects are reviewed. The prevailing paradigm is that carcinogens, particularly genotoxic compounds, have no threshold in exerting their potential for cancer induction. However, the nonthreshold hypothesis can be challenged for cancer risk assessment in humans. A recent very large-scale cooperative effort in Japan furthermore showed that the genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, forms DNA adducts and 8-hydroxy-2'-deoxyguanosine at low doses, but does not induce glutathione S-transferase placental form (GST-P) positive foci as preneoplastic lesions in rat liver (< or = 10 ppm in diet). Moreover, very low doses of a N-nitroso compound. diethylnitrosamine (DEN), were also found not to significantly induce GST-P positive foci in rat liver (< or = 0.01 ppm in drinking water). Given the direct correlation between induction of the preneoplastic lesions in the short-term and carcinomas in the longer term with different carcinogens, the results imply a practical nonobserved effect level for hepatocarcinogenicity. Similar results were also observed with so-called nongenotoxic carcinogens such as phenobarbital (PB) and p,p-dichlorodiphenyltrichloroethane (DDT), which do not exert positive effects on lesion development at very low doses. Furthermore, experiments with application of PB and DDT after treatment with DEN indicate that at very low doses (< or = 2 ppm in diet), they may even inhibit the development of GST-P positive foci. The data reviewed provide evidence that preneoplastic foci in the liver can be employed as end-point lesions in place of tumors and that exposure to very low levels of carcinogens, typical of those found in the human environment, does not necessarily present as a risk factor.

Animals↗
PubMedDate not supplied

Rapid emergence of mammary preneoplastic and malignant lesions in human c-Ha-ras proto-oncogene transgenic rats: possible application for screening of chemopreventive agents.

For comparison of mammary gland whole mounts with examination of 2 histologic sections of mammary gland, 56 Hras128 rats were intravenously injected with 50 mg/kg body weight of N-methyl-N-nitrosourea at 50 days of age and then sacrificed at days 5, 10, 15, 20, 25, and 56. Comparison of detection sensitivity between the whole mounts and histologic sections revealed no lesions apparent in whole mounts on day 10, although intraductal proliferation was clearly detected in histologic sections in 44% of treated rats. Proliferative lesions were first detected in whole mounts at a 44% incidence on day 15, while intraductal proliferations and atypical hyperplasias were apparent in the sections at 89% and 44% incidences, respectively. On day 20, atypical hyperplasias and small adenocarcinomas in histologic sections were found in almost all animals. In conclusion, examination of 2 histologic sections from mammary tissues was found to be practical for detection of small malignant lesions as early as 15 days after MNU injection, and suppressive effects of soy isoflavones were clearly evident within 20 days after carcinogen exposure. These results suggest that this model has practical utility for short-term screening of chemopreventive agents for mammary carcinogenesis.

Adenocarcinoma↗
PubMedDate not supplied

Cancer screening literature in the period 2000-2002: pointers to future research avenues.

In order to determine which areas of cancer screening are currently receiving greatest emphasis in different parts of the world a Medline search of the literature for the period 2000-2002 was performed, concentrating attention on research into all aspects of efforts for early detection of tumours, with especial attention to methodology, motivation (including awareness of utility in the general populace and in minority groups), and intervention (professional training and general education). Focus on the skin, lung, cervix, breast, ovary + endometrium, oral cavity-oesophagus, gastric, colorectal, kidney + urinary tract and prostate, demonstrated large numbers of journals to be publishing papers in the field, with 10, 33, 130, 53, 24, 21, 6, 81, 12 and 58, respectively, in the period investigated, the grand total being 259. The average numbers of papers/journal ranged from 1.0-2.4 with only 15-35% appearing in journals with wide coverage. With the exception of oral, oesophageal and gastric cancer screening, an approximately 50% contribution in all areas was made by scientists in the US, followed by Europe (31% overall,) Asia (11%) then Australasia, Central and South America and Africa (3%, 2% and 1%, respectively). Clear differences were evident with the organ regarding specific topics receiving attention, most publications concerning the lung, ovary and urological tract dealing with detection methods. With the cervix and colorectum this topic accounted for half of the papers with especial attention to the relative advantages of the PAP smear, HPV testing and direct visual acetic acid (DVA) in the one, and FOBT and endoscopy in the other. Another major focus was found to be minority attitudes to breast, prostate and cervical screening in the US, whereas only few papers were found dealing with practical intervention, targeting professionals or screenees to increase participation in screening programs. The present approach suggested a number of areas requiring more attention, not least being the need for more comprehensive reviews across organs to allow the general reader a better understanding of the overall picture, and which avenues might best reward exploration in the future.

Forecasting↗
PubMedDate not supplied

Appropriate models and an understanding of carcinogenic mechanisms--requirements for hazard risk assessment.

Given the immense variety of compounds developed for introduction into the human environment, appropriate carcinogen risk assessment is essential. One of the responsible international bodies recognized as providing a lead in this endeavour is the International Agency for Research on Cancer (IARC), primarily through the Monographs on the Evaluation of Carcinogenic Risks to Humans. However, serious allegations have recently been made that industry now has undue influence on the decisions of the IARC Workshops as to category assignment, especially concerning down-grading of risk. The contention is that too much stress is placed on mechanistic considerations which have not been sufficiently validated. Since avoidance of carcinogens in our environment is clearly of prime importance to cancer prevention, open discussion of how they should be identified is of essential significance to the APOCP. Clearly, decisions should be based solely on scientific evidence and there should be no place for politics or polemic. We have therefore looked, in what we hope is a dispassionate fashion, at the arguments offered in the recent literature, while admitting to a bias towards taking into account all the available knowledge on mechanisms of action of carcinogens and modulating agents. As scientists, generation of an understanding of this area is one of the main reasons why we receive our salaries. To blindly argue that carcinogenicity, for example at high dose in one strain of experimental animal, necessarily implies human risk at normal levels of exposure is obviously untenable. At the same time, precipitous conclusions regarding species-specific mechanisms must naturally be avoided. Both academic and industrial researchers need to apply a balanced judgement and to simply imply that any association with industrial concerns is likely to lead to irresponsible behaviour to the detriment of public health is not tenable. With regard to regulatory decision making, we should be concentrating more attention on mechanisms, rather than less, especially in light of recent findings pointing to hormesis at low doses of carcinogens, which will inevitably generate heated discussion and the charge of bias in favour of industry. The onus is on all members of the scientific community to impartially view all the epidemiological and experimental data which are available in decision-making.

Animals↗
PubMedDate not supplied

Experimental investigation of opisthorchiasis-associated cholangiocarcinoma induction in the Syrian hamster - pointers for control of the human disease.

Appropriate animal models for specific diseases in man can facilitate elucidation of mechanisms underlying tumour development and allow potential interventions and therapeutic regimens to be tested in vivo before consideration for use in the human situation. In the North-east of Thailand exceptionally high levels of cholangiocellular carcinomas (CCCs) are encountered, related to infestation with Opisthorchis viverrini liver flukes. The Syrian hamster can also be infected with metacercariae of the fluke and heavy loads of parasites cause the development of cirrhotic livers. While the presence of flukes alone does not give rise to neoplasms, large yields of cholangiofibrotic lesions and CCCs can be readily induced with additional carcinogenic insult. While removal of the parasite with the antihelminthic drug Praziquantel can protect against carcinogenesis, this is dependent on the timing of the drug administration and the efficacy of application to the human situation remains to be confirmed. The available information would suggest that interest needs to be concentrated on potential chemopreventive agents which could be administered to individuals at high risk. Furthermore, understanding of the genesis of CCCs and the characteristics of preneoplastic lesions, again as assessed in the animal model, might allow novel approaches to identification of early stage cases and effective surgical intervention.

Animals↗