Europium-152 activity induced by Hiroshima atomic bomb neutrons: comparison with the 32P, 60Co, and 152Eu activities in dosimetry system 1986 (DS86).
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Cobalt Radioisotopes↗
Biomedical subjects
K Yokoro
Publications and source records attributed to K Yokoro.
Clonogenic cells and rat mammary cancer: effects of hormones, X rays, and fission neutrons.
On Day 0, young adult female F344 rats were adrenalectomized and intrasplenically implanted with a pituitary gland and capsule containing estrone. All were thereafter given 2.5 mg deoxycorticosterone per week and the choice of saline or tap water. This treatment yields high prolactin levels and glucocorticoid deficiency (Prl+/Glc-). On Day +48, total recoverable mammary DNA was increased by more than sevenfold, tritiated thymidine uptake by nearly fourfold, and total mammary clonogens by about fivefold. Irradiation with 4, 40, and 80 cGy X rays on Day +48 increased total mammary carcinomas per rat day at risk linearly with dose, and 40 and 80 cGy significantly decreased first carcinoma latency. A dose of 40 cGy X rays on Day -1 yielded tumor latencies and frequencies insignificantly different from unirradiated controls and significantly different from the dose on Day +48. Total carcinomas per rat day at risk were better fit by a function of dose to the power 0.4 than by a linear function after exposure to 1, 10, and 20 cGy fission neutrons, and 10 and 20 cGy significantly shortened the time to appearance of the first cancer. In contrast to results with X rays, 10 cGy neutrons on Day -1 yielded tumor frequencies and latencies insignificantly different from 10 cGy neutrons on Day +48. The carcinogenic action of X rays was thus influenced by total clonogen numbers and/or proliferation rates; that of neutrons was not.
Animals↗
Effect of OK-432 on the lymphnode metastasis of MCA-sarcoma cell lines: a new therapeutic approach.
The two unique highly metastatic MCA-sarcoma cell lines have been established by the present authors. The inoculation of 1153Ln, one of the cell lines, either into footpad or subcutaneously on the back of syngeneic mice resulted in the development of metastasis exclusively in almost all lymphnodes of the body. We evaluated the therapeutic effect of a streptococcal preparation, OK-432, on the lymphnode metastasis. Two KE per mouse of OK-432 were injected intratumorally (it) at 4, 7 or 10 days after the footpad inoculation of 1153Ln. OK-432 injected it at 7 days after tumor inoculation showed an inhibition of the lymphnode metastasis. Histological findings indicated that the proliferation of lymphoid cells in the drainage node was most prominent in mice treated with OK-432 at 7 days after the tumor inoculation. A combined treatment of it and intraperitoneal (ip) injections of OK-432 significantly reduced lymphnode metastasis as compared with that of ip injection alone. This can be attributed to the fact that the activated lymphocytes induced by it-injected OK-432 exhibited a potent antimetastatic activity together with general administration (ip) of OK-432 given after surgical removal of the tumor. Low dose of total-body irradiation (TBI), known to augment the antitumor potential of tumor-bearing animals together with general application of OK-432, showed synergistic action in inhibiting tumor growth. Overall results suggest that the better antitumor effect of OK-432 can be anticipated by combination of the agent itself and with other means.
Animals↗
[Clonal evolution in tumor cell population].
Clonal evolution which characterizes malignant tumors is the consequence of two antagonizing forces acting on the tumor cell population, namely, forces of diversion and conversion. The former makes cells to diverge through genetic and epigenetic instabilities which are the built-in characteristics of malignant cells. Possible causes of genetic instability are discussed. These include mistakes in DNA synthesis by an error-prone DNA polymerase, the nucleotide pool distartion and the overreplication of replication origins, abnormal DNA repair, high rate recombination, by expression of fragile sites and possibly by expression of retrotransposons, frequent nondisjunction of chromosomes as a consequence of gene dosage inbalance, and abnormal DNA methylation. The second force makes the resulting tumor cell population with heterogenous phenotypes to converge through selection by host defence mechanisms, competition for nutrients and oxygen among tumor cells, to cell interactions within tumor and between surrounding normal tissues. Genetic tagging of tumor cells with pSV 2neo facilitates the analysis of clonal evolution which results from diversion and conversion of tumor cells. Selective growth and metastasis of a clone in a mouse sarcoma population was demonstrated. Generation of dominant clones as well as drug resistant clones in tumor can be studied with this method.
Animals↗
Carcinogenic and co-carcinogenic effects of radiation in rat mammary carcinogenesis and mouse T-cell lymphomagenesis: a review.
The importance of the promotion stage and of the physiological condition of target cells at the time of initiation is illustrated in both the rat mammary carcinogenesis and the mouse T-cell lymphomagenesis. In the former, prolactin was shown to be a powerful promoter regardless of the initiating agent. Prolactin was also found to be useful in detecting the carcinogenicity of the small doses of carcinogens; a high r.b.e. of 2.0 MeV fission spectrum neutrons was demonstrated by the application of prolactin to radiation-initiated mammary carcinogenesis in rats. In the latter, total-body irradiation involving both bone marrow and thymus facilitates chemically-initiated T-cell lymphomagenesis in mice. This could be attributed to the amplification of the cell population susceptible to a chemical carcinogen in the target tissue during the recovery phase after irradiation. The dual effect of a carcinogen, acting in the different phases of carcinogenesis was suggested by the split administration of N-nitrosoethylurea (NEU) in the induction of T-cell lymphomas. It is emphasized, through these findings, that besides the initiation by a genotoxic agent, the availability of a promoter or an inhibitor determines the fate of initiated cells, and that a modifier of target cells also plays a crucial role in the efficient induction of a tumour.
Animals↗
Europium-152 depth profile of a stone bridge pillar exposed to the Hiroshima atomic bomb: 152Eu activities for analysis of the neutron spectrum.
The 152Eu activity depth profile of a granite pillar of the Motoyasu bridge located 132 m from the Hiroshima atomic bomb hypocenter was assessed. The pillars each measured 82 cm in depth, 82 cm in width and 193 cm in height. One of the pillars was bored and 6.8-cm-diameter core samples were removed and cut into 2-cm-thick disks. Two gamma rays of 152Eu, 122 keV and 344 keV, in each disk were measured using a low background, gamma-ray spectrometer, and the activity distribution was determined as a function of depth in the granite. A concentration of stable Eu in the granite was determined by activation analysis. The specific radioactivity of 152Eu and 154Eu at the pillar surface was determined to have been 117 and 24 Bq per mg Eu, respectively, at the time of detonation. The value of 152Eu agrees within 20% of that calculated by Loewe. The depth profile of 152Eu in granite demonstrates a distinct difference from the estimates made only by thermal neutrons. Present data provide valuable information for the analysis of the neutron spectrum of the Hiroshima atomic bomb and its intensity.
Europium↗
Induction of hepatic tumors by diethylstilbestrol in N-nitrosobutylurea-initiated female rats.
The carcinogenic effect of estrogens, diethylstilbestrol (DES) and 17 beta-estradiol (E2), and its modification by N-nitrosobutylurea (NBU) were studied in female W/Fu rats. Multiple mammary tumors (MT) of medullary carcinoma type developed at a high rate following prolonged treatment with estrogens. All MTs were located adjacent to the nipple and were slow-growing. The induction rate, multiplicity and size of estrogen-induced MTs were not influenced by pretreatment with a small amount of NBU, which alone did not induce any tumor. Ten of 12 rats (82%) receiving combined treatment with NBU and DES developed hepatic tumors (HT), while no rats in other treatment groups developed HT. All HTs were multiple nodules of various sizes bulging from the liver surface, and were considered to be neoplastic nodules. A high frequency of HT development was unexpected, because independent treatment with NBU or DES alone did not induce HT in female rats. It appears that DES played a role as a carcinogen, inducing MT and pituitary tumor (PT) through its estrogenic potency (like natural estrogen, E2), while it also acted as a promoter or co-carcinogen in the induction of HT through its pharmacologic effects. These findings may be relevant to an increased frequency of liver neoplasm among women taking oral contraceptives containing synthetic estrogens.
Animals↗
Granulopoiesis in patients with congenital neutropenia.
Granulopoiesis was investigated in five patients with congenital neutropenia (CN) (one Kostmann type, four benign forms). In semisolid agar culture, the marrow cells of all five patients produced normal numbers of CFU-c (colony-forming unit-culture). The size and classification of colonies were normal. In suspension culture in vitro with exogenous colony-stimulating factor (CSF) generated from omental-conditioned medium (OMCM), the myeloid precursors of all patients could proliferate and differentiate into normal polymorphonuclear neutrophils (PMNs). But in the absence of exogenous CSF, myeloid precursors of the patient with Kostmann-type CN did not proliferate or differentiate into PMNs at all. In the four patients with benign neutropenia, however, PMNs were found even without exogenous CSF similar to normal individuals. These results suggest that patients with CN may have normal granulopoietic stem cells with normal proliferative and differentiating capacity in response to exogenous CSF. When a small amount of normal human serum was added to normal marrow cultures stimulated by exogenous CSF, the colony growth increased in a superadditive manner. The enhancing activity of serum from neutropenic patients differed from that of normal serum. Especially, the addition of serum from the patient with Kostmann type CN to normal marrow cultures did not show this enhancement effect. The sera of patients with benign neutropenia had less enhancement effect than did normal control serum. These findings might be interpreted as showing an imbalance between CSF enhancer and inhibitors in the patients' serum.
Adult↗
Generation of lymphomagenic mouse type-C viruses from radiation- or chemically-induced non-producer T-cell lymphoma cell lines infected with non-oncogenic ecotropic virus.
Highly lymphomagenic mouse type-C viruses were generated from radiation- or chemically-induced T-cell lymphoma cell lines of NFS/N mouse origin infected with a non-oncogenic ecotropic virus E4. By analysis of these progeny viruses, the following results were obtained. 1) The viruses were lymphomagenic in neonatally inoculated NFS/N and C3H/He mice and W/Fu rats but not in Balb/c and C57BL/6N mice, indicating that they possess the Fv-1n tropism of exogenously infected parent virus. 2) Lymphomagenic viruses consisted of plural viral subpopulations. Recombinant mink cell focus-inducing (MCF) and ecotropic viruses were cloned from them. Inoculation of either MCF or ecotropic virus alone or both viruses together did not cause lymphoma in NFS/N mice and there was no evidence of viral replication in the recipients. 3) Inoculation of either MCF- or ecotropic virus-infected NFS-ME cells alone did not cause lymphoma development in pre-irradiated NFS/N mice, while transplantation of both MCF- and ecotropic virus-infected NFS-ME cells resulted in the development of lymphomas of host origin. These results show that lymphomagenic MCF virus was generated through the recombination of E4 viral genome and a modified proviral DNA of endogenous viruses present in radiation- or chemically-induced lymphomas, and that an interaction or synergism of MCF and ecotropic viruses is required for MCF virus to exert lymphomagenic activity.
Animals↗
Inhibition by 3-amino-1H-1,2,4-triazole of hepatic tumorigenesis induced by diethylstilbestrol alone or combined with N-nitrosobutylurea in WF rats.
Six groups of inbred male WF rats were castrated at 40 days of age. Group 1 was given no further treatment; groups 3-6 received sc implantations of 5.0 mg diethylstilbestrol [(DES) CAS: 56-53-1]. At 50-55 days of age, groups 5 and 6 were given drinking water containing 5.0 mg N-nitrosobutylurea [(NBU) CAS: 869-01-2] per day for 30 days. After the termination of NBU treatment, groups 2, 4, and 6 were given 3-amino-1H-1,2,4-triazole (AT), considered an inhibitor of hydroperoxidases, in the drinking water throughout the experiment. Castrated male rats or rats castrated and treated with AT alone developed neither hepatic tumors nor pituitary tumors. The hepatic tumor incidence, the size and total number of hepatic tumors, and the mean liver weight were significantly reduced in rats given the DES-NBU combination and slightly reduced in rats given DES alone when AT was administered. In contrast, AT treatment did not change the pituitary tumor incidence and the mean pituitary weight. The thyroid gland weights were approximately 7-44 times greater in AT-treated groups than those in each corresponding control group. These data indicate that AT inhibited hepatic but not pituitary tumorigenesis and caused enlargement of the thyroid gland. The present study, therefore, provides evidence that the metabolic activation of DES by oxidation is involved in rat liver carcinogenesis.
Amitrole↗
[Recent findings on the mechanism of murine T-cell lymphomagenesis].
The pathogenesis of murine T-cell lymphomas, induced by radiation, chemical carcinogens or lymphomagenic retroviruses, implicates such multiple factors as the derangement of T-cell differentiation, intervention of the endogenous retroviruses, the expression of the cellular oncogenes, and so on. The application of virological, immunobiological and molecular biological techniques has opened an avenue to gaining an insight into the mechanism of the disease. Among recent achievements, data on the following aspects are presented in this review. 1) Unequivocal demonstration of the "indirect induction mechanism" of lymphoma using Thy. 1 congenic mice, 2) the presence of preleukemic cells and their evolution to leukemic cells by virtue of the thymic microenvironment, 3) search for the expression or rearrangement of v-onc and c-onc with molecular hybridization techniques, and 4) generation of lymphomagenic retrovirus from non-producer T-cell lymphoma cell lines infected with non-oncogenic endogenous ecotropic virus, which may represent the emergence of a lymphomagenic virus following leukemogenic treatments through the genetic recombination of viral genomes.
Animals↗
Synergistic effect of radiation and N-nitrosoethylurea in the induction of lymphoma in mice: cellular kinetics and carcinogenesis.
The effect of a combined treatment with radiation and N-nitrosoethylurea (NEU), or a split administration of NEU in inducing lymphoma was studied in female C57BL/6N mice. A single intragastric administration of 5 mg of NEU was only slightly lymphomagenic, inducing thymic lymphomas in 20% of mice, while the incidence was elevated to 92% if the NEU treatment was preceded (by 5 days) by 400 rad of total-body X-irradiation, which alone is seldom lymphomagenic. A high yield of lymphoma (84-93%) was also obtained if 5 mg of NEU was delivered in two split doses of 4 mg and 1 mg with a 4 day interval. Drastic injury to both the thymus and bone marrow caused by either 400 rad total-body X-irradiation or the first dose of NEU (4 mg) was followed by a vigorous regeneration within a few days. The maximum induction rate of lymphoma was obtained when the subsequent dose of NEU (1 mg) was given at the peak of DNA synthesis in the bone marrow and thymus following the first treatment. The data indicate that the principal effect of the irradiation or the first dose of NEU was to provide a susceptible cell population, and that a high yield of lymphoma was brought about through the action of the subsequent dose of NEU on a sufficient number of target cells engaged in heightened DNA synthesis.
Animals↗
High mammary carcinogenicity of neutron irradiation in rats and its promotion by prolactin.
The present study was undertaken to assess the mammary carcinogenic effect of low doses of fission and thermal neutrons in female W/Fu rats. Only 2 of 62 (3.2%) rats exposed to various doses of fission radiation alone developed mammary tumors (MT) in a 12-month observation period, whereas 21 of 63 (33.3%) similarly irradiated rats developed MT if further treated with prolactin; the lowest effective dose was 4.1 rad, which contained only 1.7 rad of fission spectrum neutrons with an average energy of 2.0 MeV. The long survival of radiation-initiated potentially malignant cells was suggested by the observation that excess numbers of MT developed in irradiated rats in whom prolactin treatment was started as late as 12 months after irradiation. The negligible contribution of gamma-rays, one component of the reactor radiations, to the rat mammary carcinogenesis was proven by a simulation experiment with 60Co gamma-rays. Thermal neutrons with an average energy of 0.025 eV were less effective than fission neutrons. The rat mammary carcinogenic effects of 180 kVp X-rays, 14.1 MeV fast neutrons, 0.025 eV thermal neutrons and 2.0 MeV fission neutrons were estimated in such a way as to compare the dose of each radiation that gave an MT incidence of 40% of that in irradiated, prolactin-treated rats. The efficiency of fission spectrum neutrons is much higher than those of other radiations; the relative biological effectiveness (RBE) of fission spectrum neutrons was 17.8 against X-rays. Based on these findings, the relevance of animal data to tumor induction in atomic bomb survivors is discussed.
Animals↗
Protective effects of progesterone and tamoxifen in estrogen-induced mammary carcinogenesis in ovariectomized W/Fu rats.
The protective effect of progesterone or tamoxifen, an antiestrogenic agent, was investigated in estrogen-induced mammary carcinogenesis. Multiple mammary tumors (MT) of tubular or medullary carcinoma type developed at a high rate following prolonged treatment of ovariectomized W/Fu rats with diethylstilbestrol or 17 beta-estradiol. All MTs were located adjacent to the nipple and were slow-growing. The induction rate, multiplicity and size of estrogen-induced MTs were reduced by the simultaneous administration of either progesterone or tamoxifen. The estrogen-induced pituitary tumorigenesis was effectively inhibited by tamoxifen treatment, but it was not affected by progesterone. The results indicated that the inhibitory effect of progesterone or tamoxifen in estrogen-induced carcinogenesis is attributable to interference with the binding of estrogen to the estrogen receptors on the target cells.
Adenoma↗
Preventive effects of antioestrogen on mammary and pituitary tumorigenesis in rats.
Six groups of inbred male Wistar/Furth (WF) rats were castrated at 40 days of age and group I received no further treatment. Groups 3 and 5 received 5.0 mg diethylstilboestrol (DES) pellets. Groups 4 and 6 were given both DES and 5.0 mg anti-oestrogen (antiE) clomiphene citrate pellets. At 50-55 days of age groups 2, 5, and 6 were exposed daily to drinking water containing 5.0 mg N-nitrosobutylurea (NBU), for 30 days. None of the castrated rats given NBU alone developed mammary or pituitary tumours (MT, PT). When antiE was administered, both MT and PT incidences were reduced in rats given DES alone or in combination with NBU. Furthermore, in antiE-treated rats receiving DES and NBU the mean number of MT per rat was also significantly decreased. Similarly a marked reduction in the mean pituitary weight was observed in antiE-treated groups. These results indicate that antiE treatment was effective in the prevention of both mammary and pituitary tumorigenesis in rats receiving DES alone or receiving a combination of DES and NBU, and its inhibitory effect on mammary tumorigenesis may be mainly due to competitive antagonism for DES-induced pituitary tumorigenesis by antiE.
Animals↗
Inhibitory effect of antiestrogen on hepatic tumorigenesis in WF rats treated with diethylstilbestrol alone or in combination with N-nitrosobutylurea.
Four groups of inbred male WF rats were castrated and received sc implantations of diethylstilbestrol [(DES) CAS: 56-53-1; alpha,alpha'-diethyl-4,4'-stilbenediol] at 40 days of age. Group I was given no further treatment; groups II and IV were treated with antiestrogen (AntiE) clomiphene citrate simultaneously with DES treatment. At 50-55 days of age, groups III and IV were given drinking water containing N-nitrosobutylurea [(NBU) CAS: 869-01-2; 1-butyl-1-nitrosourea] for 30 days. Castrated male rats or rats castrated and treated with NBU alone developed neither hepatic tumors (HT) nor pituitary tumors (PT). When AntiE was administered, incidences of HT and PT, size and the total number of HT, and mean pituitary weight were significantly reduced in rats given DES alone and in rats given DES with NBU. AntiE treatment changed the distribution in the histologic classification of hepatocellular lesions: Neoplastic nodules, instead of hepatocellular carcinomas, were predominant. The results indicate that AntiE was effective in the inhibition of hepatic and pituitary tumorigenesis associated with DES treatment. Our previous study has shown that prolactin was not involved in this hepatic tumorigenesis. Therefore, these studies provide evidence that the carcinogenic effect of DES on the liver cell is direct and that HT are regulated in development and growth by AntiE treatment.
Animals↗
Prolactin and aging: X-irradiated and estrogen-induced rat mammary tumorigenesis.
Both sexes of inbred WF rats at either 8 or 28-60 weeks of age were exposed to 200 rad whole-body radiation, 2.5 or 5.0 mg 17 beta-estradiol (E2), or both agents The female rats treated with E2 alone or with both X-rays and E2 at 8 weeks of age showed a high incidence of mammary carcinomas (MCA), a large increase in pituitary weight, and a rise in serum prolactin (PRL) levels. However, the same treatments to males did not induce MCA despite a moderate increase in both pituitary weight and serum PRL. Ovariectomy prior to E2 treatment failed to modify the occurrence of MCA or pituitary tumors. When X-rays and E2 were given to female rats at 28-60 weeks of age, pituitary weight, serum PRL levels, and the incidence of MCA were unaffected. When the E2 pellet was kept for the first 24 weeks and withdrawn during the last 12 weeks, the incidence of MCA, pituitary weight, and serum PRL was low. It was concluded that: 1) the pituitary glands of young female rats were susceptible to E2 treatment but were insensitive in older females, and 2) the occurrence of MCA in female rats appeared to be promoted by elevated PRL levels secreted by E2-induced pituitary tumors. Mammary tissue of male rats was less sensitive to PRL levels in the development of MCA.
Aging↗
Effects of 17 beta-estradiol and diethylstilbestrol on concurrent development of hepatic, mammary, and pituitary tumors in WF rats: evidence for differential effect on liver.
17 beta-Estradiol [(E2) CAS: 50-28-2; estradiol] and diethylstilbestrol [(DES) CAS: 56-53-1; alpha-alpha'-diethyl-4,4'-stilbenediol] were compared to determine their tumor-inducing abilities in tissue. After castration at 40 days of age, inbred male WF rats received a pellet of either 5.0 mg DES or 5.0 mg E2. Approximately half of the rats that had been given DES or E2 were further given at 50-55 days of age 5.0 mg N-nitrosobutylurea [(NBU) CAS: 869-01-2; 1-butyl-1-nitrosourea] in their drinking water each day for 30 days. None of the castrated rats given E2 alone developed hepatic tumors (HT). Even further addition of NBU did not elicit any HT. Conversely, E2 treatment as well as DES treatment, whether administrated alone or in combination with NBU, resulted in an increase in the incidence of pituitary tumors (PT) and in the mean pituitary weight. The data indicate that E2 was ineffective in inducing HT in castrated male rats, whereas E2 showed an ability to induce PT similar to that of DES. In addition, E2 was not as able to induce as many mammary tumors as DES was able to induce. There was no significant synergism between E2 and NBU in contrast to that between DES and NBU in mammary tumorigenesis, whereas these two estrogens had a similar effect in causing an increase in the pituitary weight. This study, therefore, suggests that the carcinogenic effect of estrogens may not always correlate with their estrogenic effect and further confirms the noninvolvement of prolactin in hepatic tumorigenesis.
Animals↗