Biomedical subjects

M Kodama

Publications and source records attributed to M Kodama.

At least 685 records · Page 38Linked to original sources

PubMedDate not supplied

In search of the cause of gastric cancer.

The purpose of this review was to describe the historical development of each epidemiology, experimental pathology, endocrinology (including vitaminology), and thermodynamics surrounding the genesis of gastric cancer in humans and non-human mammals. Epidemiological studies from other and our laboratories were unanimous in counting the intake of carbohydrate-rich and salty diet with vitamin C deficiency as the risk factor of key importance. Information from experimental pathology suggested the possible implication of some nitroso compounds in a subject with atrophic gastritis and/or in a state of vitamin C deficiency of which the establishment should have led to a perturbation of the steroid milieu of the host. In endocrinology, the association of a specific steroid disorder (depression of androgen and progestin combined with glucocorticoid excess in urine) with gastric cancer, as noted in the case-control study of this neoplasia, was reproduced in mice maintained under biased nutritional conditions. The use of scurvy-prone ODS rats was found useful in elucidating the interrelation between vitamin C and steroid metabolism. Finally, thermodynamic analysis of the data distribution of gastric cancer risk parameter of both sexes revealed the presence of an interaction between oncogene activation and tumor suppressor gene inactivation in the course of the maintenance of the positive correlation with male predominance between male gastric cancer and female gastric cancer as regards the changes of age-adjusted incidence rate (AAIR) in space. In conclusion, all of the information available in the field of gastric cancer etiology is in support of the pertinence of the steroid criminal hypothesis of gastric cancer in humans and in non-human mammals.

Animals↗

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Kinetics of cytokine gene expression during the in vitro CTL induction against a murine nonimmunogenic tumor.

BACKGROUND: The study of the local environment around tumors, including cellular and endogenous cytokine kinetics may improve our understanding of the biological process occurring during the CTL induction. MATERIALS AND METHODS: The expression kinetics of ten cytokine genes and immune cell subsets were examined by a RT-PCR and immunohistochemistry using a nonimmunogenic murine tumor and its immunogenic variant (A7). RESULTS: In a mixed lymphocyte-parent tumor cell culture (MLTC) using in vivo A7-immunized spleen cells, where CTL induction was confirmed on day 5 of cultivation, IL-6 gene expression was promptly activated at 12 h, IL-2 and IL-4 gene expression was prominently up-regulated on days 1 and 2, and then IL-10 and TGF-beta gene expression was down-regulated from day 2 onward. In contrast, in a MLTC using non-immunized spleen cells (a CTL non-induction model), no prominent upregulation of the IL-6, IL-2 or IL-4 gene was detected, and expression of the IL-10 and TGF-beta genes increased steadily. Although numerous dendritic cells were observed in the A7 immunized spleen tissue, lower numbers of dendritic cells were evident in the non-immunized spleen tissue. CONCLUSIONS: A cellular environment that includes the presence of dendritic cells and a cytokine environment that involves the timely production of IL-6, IL-2, and IL-4, and subsequent inhibition of the immunosuppressive cytokines IL-10 and TGF-beta, appear to play an important role in induction of CTL in this model.

Animals↗

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Intertumor linkage of age-adjusted incidence rate in 15 human neoplasias of both sexes.

We report here that the application of the least square method of Gauss to the log-transformed age-adjusted incidence rate changes in time and space, as tested with either the male-female or the female-male tumor pairs for each of 15 tumor entities, has revealed the presence of intertumor linkage that was conditioning the changes of two cancer risk parameters to let them fit to the equilibrium model with close resemblance to the chemical equilibrium model. The dissimilarity of the cancer risk equilibrium model to the chemical equilibrium model--topological dissociation between the equilibrium model of centripetal force (r = -1.000) and that of centrifugal force (r = +1.000)--was discussed in the light of the concept of the oncogene activation-tumor suppressor gene inactivation. The proposed network hypothesis of human neoplasia found supporting evidence in the corresponding changes of the statistical features of human neoplasias with and without sex discrimination of cancer risk.

Age Distribution↗

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Oncogene activation and tumor suppressor gene inactivation find their sites of expression in the changes in time and space of the age-adjusted cancer incidence rate.

The purpose of the present investigation is to elucidate the relation between the distribution pattern of the age-adjusted incidence rate (AAIR) changes in time and space of 15 tumors of bothe sexes and the locations of centers of centripetal-(oncogene type) and centrifugal-(tumoe suppressor gene type) forces. The fitness of the observed log AAIR data sets to the oncogene type- and the tumor suppressor gene type-equilibrium models and the locations of 2 force centers were calculated by applying the least square method of Gauss to log AAIR pair data series with and without topological data manipulations, which are so designed as to let log AAIR pair data series fit to 2 variant (x, y) frameworks, the Rect-coordinates and the Para-coordinates. The 2 variant (x, y) coordinates are defined each as an (x, y) framework with its X axis crossed at a right angle to the regression line of the original log AAIR data (the Rect-coordinates) and as another framework with its X axis run in parallel with the regression line of the original log AAIR pair data series (the Para-coordinates). The fitness test of log AAIR data series to either the oncogene activation type equilibrium model (r = -1.000) or the tumor suppressor gene inactivation type (r = 1.000) was conducted for each of the male-female type pair data and the female-male type data, for each of log AAIR changes in space and log AAIR changes in time, and for each of the 3 (x, y) frameworks in a given neoplasia of both sexes. The results obtained are given as follows: 1) The positivity rates of the fitness test to the oncogene type equilibrium model and the tumor suppressor gene type model were each 63.3% and 56.7% with the log AAIR changes in space, and 73.3% and 73.3% with log AAIR changes in time, as tested in 15 human neoplasias of both sexes. 2) Evidence was presented to indicate that the clearance of oncogene activation and tumor suppressor gene inactivation is the sine qua non premise of carciniogenesis. 3) The r profile in which the correlation coefficient r, a measure of fitness to the 2 equilibrium models, is converted to either +(r > 0) or -(0 > r) for each of the original-, the Rect-, and the Para-coordinates was found to be informative in identifying a group of tumors with sex discrimination of cancer risk (log AAIR changes in space) or another group of environmental hormone-linked tumors (log AAIR changes in time and space)--a finding to indicate that the r-profile of a given tumor, when compared with other neoplasias, may provide a clue to investigating the biological behavior of the tumor. 4) The recent risk increase of skin cancer of both sexes, being classified as an example of environmental hormone-linked neoplasias, was found to commit its ascension of cancer risk along the direction of the centrifugal forces of the time- and space-linked tumor suppressor gene inactivation plotted in the 2-dimension diagram. In conclusion, the centripetal force of oncogene activation and centrifugal force of tumor suppressor gene inactivation found their sites of expression in the distribution pattern of a cancer risk parameter, log AAIR, of a given neoplasias of both sexes on the 2-dimension diagram. The application of the least square method of Gauss to the log AAIR changes in time and space, and also with and without topological modulations of the original sets, when presented in terms of the r-profile, was found to be informative in understanding behavioral characteristics of human neoplaisias.

Age Factors↗

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The nature of tamoxifen action in the control of female breast cancer.

Tamoxifen, now in use in the breast cancer clinic worldwide, was a study subject of controversy showing an estrogenic property on one occasion and an anti-estrogenic property on another occasion. The outcomes of 4 case-control studies of tamoxifen use were disclosed through 4 publications in 1998. The contents of these reports were intriguing, not only to surgeons of breast cancer clinics, but also to researchers of oncological science in general. The results of 4 research groups, being compatible with each other, were summarized in succession as follows: a) long-term use of tamoxifen reduced the occurrence of estrogen receptor (ER)-positive tumors by 69%, but no difference in the occurrence of ER(-) tumors was seen; b) the incidence of endometrial cancer was increased in the tamoxifen group; c) in women who did not have breast cancer and who had had a hysterectomy, there was no difference of breast cancer occurrence between the placebo- and tamoxifen-arms. Nevertheless, there was a statistically significant reduction of breast cancer among women receiving tamoxifen who also used hormone-replacement therapy during the trial; d) there was also no case-control difference of breast cancer occurrence between tamoxifen- and placebo-groups, when tested in a healthy population with a strong family history; e) the beneficial effect of long term use of tamoxifen in patients with early breast cancer, as assessed in terms of recurrence reduction, survival improvement and suppression of a contralateral tumor growth, was restricted to ER(+) patients; f) there was a positive correlation between the duration of tamoxifen use and the occurrence of endometrial cancer. All these observations provide strong support to the concept of the steroid criminal theory of human carcinogenesis in general. On the basis of both tamoxifen data and other information surrounding the hormonal aspect of human carcinogenesis of multiple tumors including breast cancer, we propose that the steroid generating system, as linked to the ever changing environment, plays a cardinal role as the transmitter of steroidal signals that can be taken as a "go" sign by the local oncogene-tumor suppressor gene complex of one target tissue and as a "stop" sign by that of another target tissue. The fitness of the tamoxifen data to the steroid carcinogenesis concept was discussed in the light of experimental pathology of chemical carcinogens, including the mammocarcinogen 7,12-dimethyl-benz(a)anthracene.

9,10-Dimethyl-1,2-benzanthracene↗

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Down-regulation of IL-18 receptor in cancer patients: its clinical significance.

Interleukin-18 (IL-18) is a powerful inducer of interferon-gamma (IFN-gamma), a key immunoregulatory cytokine. Cellular immune responsiveness, as measured by IL-18-induced IFN-gamma production from peripheral blood mononuclear cells (PBMCs) in ELISA assay, was evaluated in 10 patients with advanced cancer and in 10 normal controls. Supernatant levels of IFN-gamma were detected at 2 hours after PBMCs culture and markedly increased thereafter in healthy volunteers. In contrast, IFN-gamma production in cancer patients was not detected during the culture period (0-72 hours). We also measured IL-18-stimulated IL-12 production in healthy volunteers and null response was observed in cancer-bearing patients. Next, we studied mRNA expressions of IL-18 receptor (IL-18R) and IFN-gamma in PBMCs in cancer patients and healthy volunteers by RT-PCR assay. Both mRNA levels of IL-18R and IFN-gamma were significantly decreased in cancer-bearing patients compared with normal controls. These results suggested that IL-18 responsiveness for IFN-gamma production in cancer-bearing patients was impaired. Using flow cytometric analysis, we studied T-cell subsets, CD3- CD56+ (NK cell), CD3+ CD45RO+ (memory T-cell), CD3+ CD95+ (Fas+ T-cell), CD3+ CD4+ (helper T-cell), CD3+ CD8+ (cytotoxic T-cell: CTL) and CD3+ V alpha24+ (NKT-cell), in cancer patients and normal controls. The NK and cytotoxic T-cells significantly decreased and NKT-cells had decreased tendency in cancer patients compared with normal controls. In contrast, memory T cells, Fas+ T-cells and helper T-cells were all significantly increased in cancer patients compared with normal controls. These results suggested that the underlying mechanism of impaired IL-18 responsiveness in PBMCs from cancer-bearing patients was, at least in part, ascribed to a drastic decrease of NK cells and CTL which constitutively and highly express IL-18R and also attributed to null production of IL-12 which up-regulates IL-18R.

Adult↗

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Cyclosporin A is a hormonal immunomodulator. I. Human study.

The immunosuppressant Cyclosporin A (CS) is known to induce 2 hormonal disorders as side effects of its long-term use: gynecomastia in male subjects and hirsutism in female subjects. The present study was started to investigate the problem of whether or not the above steroid-mimetic actions of CS are to be related to the immunosuppressive effect of that substance. Practically, a case-control comparison of 14 urinary steroid excretions was made for each sex with healthy controls and kidney transplant recipients undergoing CS-free and CS-dependent immunosuppressive treatments on the one hand, and the success rate of kidney transplantation was compared between the CS-free treatment group and the CS-dependent treatment group on the other hand. The results obtained are follows: 1) Both the CS-free- and CS-dependent-treatments produced a general depression of all androgens, progestins and corticosteroids in the urine. The suppressive effect on urinary steroid excretions was more marked in the latter than in the former. Under the same CS-free treatment, the excretion of tetrahydrocortisol (THF) was intact in male patients and was significantly depressed in female patients. 2) A remarkable difference between the 2 immunosuppressive treatment groups was found in the ratio of urinary androsterone (AD) to urinary THF, an index of androgen to glucocorticoid balance: the praxis of CS-free treatment significantly depressed log AD/THF in patients of both sexes, the ratio being much higher in normal males than in normal females.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗

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Relation between the hormonal and epidemiological aspects of ovarian cancer patients in Japan.

We compared the hormonal and epidemiological aspects of ovarian cancer patients in search of the etiology of this neoplasia. Case-control studies of Japanese women with and without cancer were conducted in parallel, with regard to both the excretion of 14 urinary steroids and the pertinent physical and physiological parameters. The results obtained are as follows: 1) premenopausal ovarian cancer patients before and after radical ovariectomy and postmenopausal-postoperative patients were associated with a specified steroid deviation profile characterized by a combination of general depression of androgens, progestins and corticosteroids with sole rescue of tetrahydrocortisol (THF) in urine. 2) The deviation profile of postmenopausal-preoperative cancer patients was distinguished from the 3 partner profiles by its preservation of normalcy in the excretions of androgen and progestin in urine. 3) Ovarian cancer patients were associated with growth retardation, when compared with urban healthy controls and patients with either breast cancer or endometrial cancer by the age-matching method. Ovarian cancer patients were also less fertile than age-matched normal controls, and were as infertile as age-matched patients with either breast cancer or endometrial cancer. 4) Epidemiological evidence was presented to suggest that the incidence of ovarian cancer in Japan was increasing in parallel with the recent increase of social tension in Japan. The possible relevance of the hormonal characteristics of ovarian cancer patients to both the epidemiological characteristics of the same cancer patients and the genesis of this neoplasia is discussed in the light of the 2-step carcinogenesis theory.

Body Height↗

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Does surgical stress cause tumor metastasis?

The purpose of this study was to test the validity of our working hypothesis that the stress of radical surgery may affect the prognosis of a cancer patient by precipitating hematogenous tumor metastasis, and that enhancement of this type of tumor metastasis is mediated by an increase of glucocorticoid activity that is induced in a cancer patient by surgical stress. Practically, we looked for the presence of glucocorticosteroid excess in cervical cancer patients in the course of radical surgery, and also tested the possible impact of glucocorticoid excess on the development of tumor metastasis in mice with i.v. inoculated Ehrlich ascites clone 1 tumor cells. The results obtained indicated that: 1) a state of glucocorticoid excess was observed in cancer patients at an early stage of postoperative convalescence. 2) Development of lung metastasis of blood-borne Ehrlich ascites tumor cells was facilitated in mice by hydrocortisone pretreatment--a substitute for surgical stress conditioning. 3) In the enhancement of lung metastasis, the hormone was found to induce constriction of the lung capillary lumen on the one hand, and acceleration of microvillus growth of the tumor cell surface on the other hand two morphological changes that may facilitate intrapulmonary retention of tumor cells. 4) Cyclophosphamide, as tested in a series of adjuvant chemotherapy experiments, was effective in either retarding or arresting the progress of tumor metastasis in hydrocortisone-conditioned mice. The possible impact of surgical stress on the spread of blood-borne tumor cells to the lung and liver, as well as on the therapeutic effect of cyclophosphamide for the prevention of postoperative micrometastasis, is discussed in the light of glucocorticoid actions on its target tissues.

Animals↗

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Relation between the hormonal and epidemiological aspects of esophageal cancer in Japan.

Esophageal cancer with endemic distribution of high-risk areas in the world is also known to be more prevalent in the male--and in the aged-populations than in their counterparts. The hormonal characteristics of esophageal cancer patients and the geographical distribution of high and low-risk areas in Japan were comparatively investigated in search of the etiology of this neoplasia. A case-control study of 14 urinary steroids indicated that cancer patients of both sexes were associated with an acceleration of cortisone to hydrocortisone conversion within their bodies. Evidence was presented to suggest that the above state of glucocorticoid excess could be related to the production of hyperplasia as well as malignant transformation in the epithelial cells of the esophagus. The 10 highest risk areas and the 7 lowest risk areas were clearly separated by the 2 fault lines of the Japan Islands, a finding to suggest that some microelements of the soil play a role in conditioning the cancer risk. The possible linkage of the observed hormonal characteristics of Japanese patients to both the geochemistry of the soil and the genesis of this neoplasia is discussed in the light of the competitive relationship between the intake of vitamin C and endogenous nitrosation.

Adult↗

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Differential surface structures of invasive and non-invasive Ehrlich ascites tumor cell lines with special reference to the effect of hydrocortisone treatment.

The purpose of this study is to investigate the relation between the fine structure of the tumor cell surface and the tumor malignancy by scanning electron microscopy. Practically, comparison was made between the invasive Ehrlich ascites clone 1 tumor and the non-invasive Ehrlich ascites clone 3 tumor, and also between the 4th postinoculation day and the 6th postinoculation day as regards the growth of microvilli on the cell surface. On the 4th postinoculation day, an invasive clone 1 tumor cell was indistinguishable from a non-invasive clone tumor cell because of their common paucity of microvilli development. On the 6th postinoculation day, the former was associated with exuberant growth of microvilli, and was clearly distinguished from the latter in which the density of microvilli stayed low as before. The appearance of dense microvilli growth in the invasive clone 1 tumor cells chronologically coincided with the stage of fatal bleeding into the abdominal cavity. Hydrocortisone with a dose of 1 mg/mouse, when given subcutaneously to a tumor-bearing mouse on the 4th postinoculation day, stimulated the development of microvilli in both clone 1 and clone 3 tumors. The enhancing effect of the hormone on this process was detectable 2 hours after hormone injection. It was indicated that the dense growth of microvilli in the clone 1 tumor facilitated its tumor invasion into visceral organs, and that the enhancing effect of hydrocortisone on microvilli development was to be related to the promotion of malignant transformation. The possible implications of glucocorticoid in mammocarcinogenesis are discussed from the point of view of comparative endocrinology.

Animals↗

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Cyclosporin A is a hormonal immunomodulator. II. Mouse study.

The present study investigated the effects of hydrocortisone (HCA) and cyclosporin A (CS) on the wet weights of various target tissues and on the plasma levels of 6 steroids and cholesterol (CH) in Swiss mice of both sexes. The effects of CS on the weights of the spleen and forestomach, as viewed from their steroid dependencies in weight change, were different for each tissue and for each sex: CS effect on the male spleen was characterized as a mixture of a major androgenic element and a minor corticosteroid-like element, whereas that on the female spleen was scored as purely androgenic. Similarly, CS effects on the male and female forestomachs were interpreted respectively as estrogenic and androgenic in nature. Both the sole use of HCA (CS-free treatment) and the combined use of HCA and CS (CS-aided treatment) increased plasma testosterone (T) and plasma CH at the expense of other plasma steroids, though minor differences were detectable between the two treatments as regards the deviation profiles of 6 steroids and cholesterol with mice of both sexes. Plasma hydrocortisone (F) in males and plasma estradiol (E2) in females were consistently resistant to the depressing effects of the 2 immunosuppressants. In conclusion, the effect of CS on the mouse immune system, as judged from the response of the spleen, was to create a state of hyperandrogenism in favor of the production of immune unresponsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗

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The genesis of breast cancer is a two-step phenomenon. I. Differential effects of aging on the cancer incidence in the United Kingdom and Japan.

The present study investigated comparatively the relation between host age and age-specific incidence rate (ASIR) of breast cancer in the United Kingdom and Japan. Comparison was also made between breast cancer and 5 non-mammary neoplasias as regards the cancer incidence/age profile. The results obtained are as follows: 1) the ASIR profile of breast cancer in the age range of 22.5 years to 47.5 years was characterized by a rapid rise versus age which was common between the United Kingdom and Japan. By use of the log-log plot, the growth of breast cancer risk was found to be quasi-exponential, and the above time range was termed the stage of exponential growth. 2) From 47.5 years of age on, the stage of stagnation ensued: the ASIR for the United Kingdom kept on rising with a much reduced inclination, whereas that for Japan followed the way of gradual decline. In the log-log plot, the junction between the 2 stages was recognized as a distinct break point. 3) A similar two-stage structure was found in the ASIR profiles of cancers of the stomach, lung, cervix uteri, and corpus uteri. The break points for the first 2 neoplasias were located at senescent ages, and those for cervical cancer and endometrial cancer were located at the pre- and peri-menopausal ages respectively (27.5-32.5 and 52.5 years). The profile of lymphoid leukemia gave 2 distinct surges at the ages of infancy and senescence, regardless of the country. The significance of the break point in the ASIR profile of breast cancer was discussed in relation to the two-step carcinogenesis theory.

Adult↗

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The genesis of breast cancer is a two-step phenomenon. II. Dissociation of two biomarkers in cancer patients from a low risk area of Japan.

The association of dual steroidal disorders with breast cancer, as proposed on the basis of a case-control study in a high risk area of Japan, was tested for its validity in breast cancer patients from a low risk area of Japan. A state of glucocorticoid excess, the first hormonal trait of a breast cancer patient, was assessed using a urinary steroid parameter (a reduction of the androsterone to tetrahydrocortisol ratio by definition), and/or using a physical parameter (an elevation of the waist to hip circumference ratio by definition). Inclination to ovulation failure, the second hormonal trait, was tested using another urinary steroid parameter (a specified disorder of progestin metabolism by definition), and/or a demographic parameter (a reduction in the number of live births by definition). Results obtained are as follows: 1) premenopausal breast cancer patients from a low risk area were found to have the second trait but not the first trait, as tested using 2 parameters for each trait. 2) Postmenopausal cancer patients from a low risk area as well as pre- and post-menopausal cancer patients from a high risk area had both the 2 hormonal traits. 3) There was no discrepancy of results between any 2 test systems with the identification of 2 hormonal traits in 4 cancer patient groups. The significance of the dissociation of 2 hormonal traits, as observed in premenopausal cancer patients from a low risk area, is discussed in favor of the two-step carcinogenesis theory. Possible interaction of heredity and environment in the genesis of breast cancer is also taken into consideration.

Adrenal Cortex Hormones↗

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Comparative genetics of host response to N-methyl-N'-nitro-N-nitrosoguanidine. II. Inverse relationship between tumor susceptibility and salt-hydrocortisone conditioned acceleration of water turnover in rodents.

The purpose of this study was to investigate the nature of the action of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as the modulator of gene expression. Practically, both the acceleration of daily liquid consumption following salt-hydrocortisone conditioning (sea water adaptation phenomenon) and the suppressive effect of MNNG on that gene expression were comparatively investigated among Wistar rats of both sexes, Buffalo rats of both sexes and Swiss/ICR mice of both sexes. Results obtained are as follows: 1) the responsiveness to the salt-hydrocortisone conditioning, as assessed in terms of weight-adjusted liquid consumption, decreased in the order of female Swiss mice greater than male Swiss mice greater than Buffalo rats of both sexes greater than female Wistar rats greater than male Wistar rats, a finding which indicates that an inverse relationship exists between the expression of the sea water adaptation gene and that of putative stomach proto-oncogene. 2) Additional MNNG conditioning (provision of MNNG drink) eradicated the accelerating effect of the salt-hydrocortisone conditioning on the water turnover of a rodent. 3) Evidence was presented to indicate that MNNG acted as an antiandrogen in expressing the above effect. In conclusion, our findings are taken as evidence to support the proposition that the sea water adaptation gene and the stomach proto-oncogene compete with each other in the possession of one common MNNG-sensitive (and/or steroid-sensitive) enhancer gene in their gene expressions.

Adaptation, Physiological↗

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Comparative genetics of host response to N-methyl 1-N'-nitro-N-nitrosoguanidine. I. A lack of tumor production in the glandular stomach of Swiss mouse.

The present study investigated the effects of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) drink and 3 maintenance diets on both the survival and the glandular stomach morphology in a total of 480 Swiss/ICR mice. The MNNG conditioning was practised in one half of the mice for the first 8 months. The maintenance of mice on the standard (MF) diet, the rice-rich (R) diet or the rice- and salt-rich (RS) diet was continued for 12 months. The results obtained are as follows: 1) Many mice in the MNNG-conditioned groups experienced fatal bleeding into the small intestine before the termination of the feeding experiment. There was no sign of tumor formation in their digestive canals. The bleeding deaths took place more often in the MF- and RS- diet groups than in the R-diet groups, and started to appear earlier in males than in females within the MF-diet groups. 2) The tendency to gastric atophy, as assessed in terms of the wet weight of mouse glandular stomach as well as the quantitation of histological changes of the same organ in the one-year survivors, progressed in the order of the MF-diet groups, the R-diet groups and the RS-diet groups. 3) The effect of MNNG drink on the mouse glandular stomach morphology was bidirectional: it increased the incidence of advanced atrophy (and/or decreased the incidence of advanced hyperplasia) in the MF- and R-diet groups, and rather reduced the atrophy-oriented effect of the diet on stomach morphology in the RS-diet groups. 4) The above-mentioned effects of 3 maintenance diets and MNNG drink were more prominent in males than in females. 5) No neoplastic change was detected in the glandular stomachs of the one-year survivors with and without MNNG conditioning. 6) Evidence was presented to indicate that MNNG behaved as a quasi-antiandrogen in inducing the morphological changes of mouse glandular stomach.

Animals↗

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Interrelation between Western type cancers and non-Western type cancers as regards their risk variation in time and space. IV. Hormonal transition of Japanese women from the pro-cervical cancer age through the pro-endometrial cancer age to the pro-hypogonadism age.

Chronological trend of urinary steroid excretions in Japanese women was investigated during the period of June 1972 to August 1986 using healthy women of urban and rural origins, patients with breast cancer and patients with either cervical cancer or endometrial cancer. The excretions of 14 neutral steroids were estimated by gas liquid chromatography, and the obtained data were tentatively correlated with the epidemiological backgrounds. In the course of the chronological transition from the 1st stage (1972-1974) to the 2nd stage (1975-79), the urinary steroid pattern of Japanese women with and without cancer experienced a common change to produce specific deviations that were in agreement with the hormonal characteristics of a pill user or of an endometrial cancer patient. At the 3rd stage (1980-86), patients with either cervical cancer or endometrial cancer were distinguished from 1st stage controls by non-specific depression of all androgens, progestins and corticosteroids in urine. Throughout the whole period, both the risk for cervical cancer and the reproductive activity (birth rate) were found to decrease continuously in Japanese women. Evidence was presented to suggest that the above deterioration of the hormonal environment in Japanese women could be related to the stress of modern life rather than to defects in the diet. On the basis of the above findings, the 1st, 2nd and 3rd stages of our investigation were tentatively termed the pro-cervical cancer age, the pro-endometrial cancer age and the pro-hypogonadism age. The relation between the chronological change of urinary steroids and that of the epidemiological background was analyzed from the view point of population ecology.

Age Factors↗

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Is N-methyl-N'-nitro-N-nitrosoguanidine a hormonal carcinogen? (Review).

The hormonal aspect of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) is discussed in relation to its carcinogenic potency for the gastric epithelium. The action of MNNG, as assessed in terms of a) the affinities for both the glucocorticoid receptor and androgen receptor of mouse, b) the effects on the turnover of hydrocortisone and dihydrotestosterone in the glandular stomach of mouse, c) the induction of ornithine decarboxylase in the same tissue, and d) the interfering effect on the hydrocortisone - linked acceleration of water turnover at the whole body level of a mouse, points to the steroid-mimetic nature of the carcinogen. It is suggested that MNNG may behave like an androgen antagonist on the one hand, and like a chimera between glucocorticoid agonist and glycocorticoid antagonist on the other hand. The proposition that a chemical carcinogen may have an interplay with the steroid and thyroid hormone receptor superfamily in the induction of malignant transformation is reviewed in the light of recent progress of steroid receptor biology.

Animals↗