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At least 19 recordsLinked to original sources
PubMed1979

Study of the anti-tumor effect of polypeptide pineal extract.

Bovine pineal polypeptide extract (PPE) exerted an anti-tumor effect on mouse-transplantable tumors: mammary cancer (RSM), squamous cell cervical carcinoma (SCC), hepatoma-22a and lympholeukemia LIO-1, and had no effect on Harding-Passey melanoma and leukemia L-1210. It was shown that PPE possessed the ability to decrease the incidence of DMBA-induced mammary adenocarcinomas in rats. The daily administration of 0.5 mg PPE prolonged the life span of rats by 25% and failed to influence spontaneous tumor development. The arguments in favor of a possible mechanism of anti-tumor action of the pineal gland are submitted. It is suggested that the anti-tumor effect of PPE may occur when the syndrome of cancrophilia is induced by tumor transplantation or chemical carcinogens.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1985

Immunological identity of a 60 kd oncofetal protein induced in rats by chemical carcinogens and released by transformed cells.

A 60,000 dalton (60 kd) oncofetal protein was previously shown to be produced by tumors in tumor-bearing rats and by target tissues within 3 weeks of carcinogen treatment. The factor is released to and accumulates in the blood in vivo and in the conditioned medium of cultured transformed cells in vitro. A polyclonal antibody produced against the 60 kd factor purified from the plasma of a rat carrying the N-2-fluorenylphthalamic acid-induced transplantable Hepatoma 7777, was tested against the 60 kd factor from various sources. Based on the results of immunoprecipitation of biochemical activity associated with the 60 kd factor, it was determined that these anti-60 kd antibodies cross-reacted with the factor released by a dimethylbenzanthracene-induced rat mammary carcinoma, with the factor in rat tumor cytosol and with rat spontaneous lymphoma cells, but not with a 60 kd factor isolated from pooled cancer patient plasma. Furthermore, these antibodies cross-reacted with the 60 kd factor induced within 21 days of treatment of the rats with a range of carcinogens from 8 chemical structural groups. The anti-60 kd factor antibodies did not cross-react with a 35 kd factor having similar biochemical activity found in normal adult cells.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1979

Ceruloplasmin elevation and synthesis in rats with transplantable tumors.

In rats with transplantable mammary or hepatic tumors, plasma ceruloplasmin oxidase activity was increased 50--200%. This occurred progressively with tumors weighing 0.3% of body weight of more, and did not occur upon sham operation or implantation of normal tissue. Incorporation of [3H]-leucine indicated a specific enhancement of ceruloplasmin synthesis in the tumor-bearing rats, and a greater state of activation of the enzyme was also observed. The mechanism of the increase in ceruloplasmin levels in rats and humans with cancer thus appears to involve increased synthesis and activation of the enzyme.

Animals↗
PubMed1995

Genetic alterations in HCA-induced tumors.

Accumulating evidence from molecular oncology indicates that carcinogens may induce tumors through characteristic mutations in characteristic genes for each agent. Identification of specific mutations induced by heterocyclic amines (HCAs), food-borne carcinogens, should facilitate risk assessment of HCAs in man. Identification of characteristic genes affected by HCAs will lead to identification of the genes involved in human carcinogenesis. We therefore examined tumors induced by various HCAs from these two viewpoints. With regard to forestomach tumors induced in CDF1 mice by 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), mutations of Ha-ras and p53 were observed in four of eight and two of four tumors, respectively. One papilloma examined had mutations in both Ha-ras and p53, whereas two carcinomas had only one or the other. For Zymbal gland tumors induced in F344 rats by IQ, mutations of Ha- or Ki-ras were observed in both of two papillomas and in 10 of 13 squamous cell carcinomas (SCCs), while p53 mutations were limited to only four of the SCCs. The ras mutation was thus suggested to be an early event, while p53 mutation was more associated with malignancy. In liver tumors induced in F344 rats by 2-amino-3,8-dimethylimidazo[4, 5-f]quinoxaline (MeIQx), mutations of p53 were observed in one of two moderately-differentiated and two of two poorly-differentiated hepatocellular carcinomas (HCCs). No such changes were found in any of nine well-differentiated HCCs, suggesting p53 mutation to be a very late event. In colon tumors induced in F344 rats by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) (nine adenocarcinomas), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) (two adenomas and nine adenocarcinomas), or 2-amino-6-methyldipyrido[1,2-a:3', 2'-d]imidazole (Glu-P-1) (seven adenocarcinomas), a Ki-ras mutation was found in only one Glu-P-1-induced adenocarcinoma. No p53 mutations could be detected. In mammary gland carcinomas induced in F344 rats by PhIP, Ha-ras was activated in three of 17 carcinomas and p53 was mutated in one of 10 carcinomas. We therefore concluded that other genes were involved in colon and mammary carcinomas. G:C base pairs were involved in all 42 positive cases of the present study, and 36 of them were guanine base mutations. This indicates that the changes in IQ, MeIQx, PhIP and Glu-P-1 tumors were mainly caused by non-transcribed strand modifications through their major DNA adducts, N2-(guanin-8-yl)HCAs. Ha-ras mutations in the forestomach tumors induced by MeIQ were all G to T transversions at the second position of codon 13. Mutation sites of p53 did not appear to be specific in the forestomach, Zymbal gland and liver tumors.

Animals↗
PubMed1984

Responses of bone marrow gamma-glutamyltranspeptidase and alkaline phosphatase in vitro to tumor-elaborated granulocytopoietic factors.

Evidence has been obtained for the humoral mediation of the recently noted tumor-induced rise of the host bone marrow gamma-glutamyltranspeptidase (gamma GT) and alkaline phosphatase (AP) content in vivo: normal rat bone marrow suspensions, if incubated for 18 hr to 3 days with serum from mammary carcinoma hosts, show 2- to 8-fold elevations (per cell) of the same 2 enzymes. The active substance(s) is in the acid-stable, HCI-ethanol-soluble polypeptide fraction of the mammary carcinoma extract, and of the hosts' blood serum. The larger the size of the neoplasm, and the faster its growth rate, the greater the effect of the host serum on the gamma GT and AP of the normal bone marrow cells. In host rats in vivo, this response is followed by increases in the number (as well as the gamma GT and AP content) of circulating granulocytes. Therefore, a positive response on the part of these enzymes in the bone marrow suspension was also sought, and found, upon incubation with preparations which enhance granulocyte colony formation in agar cultures (i.e., colony-stimulating factor and serum from endotoxin-treated rats). The results indicate: (a) that the increase in gamma GT and AP is a necessary prelude to stimulation of granulocyte multiplication by appropriate growth factors; and (b) that measurement of these enzymes in the short-term liquid culture offers a biochemical test for such factors elaborated by cancers or in nonneoplastic conditions.

Alkaline Phosphatase↗
PubMed2002

Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy.

Tumors can recur years after treatment, and breast cancer is especially noted for long periods of dormancy. The status of the cancer during this period is poorly understood. As a model to study mechanisms of dormancy, we used murine D2.0R mammary carcinoma cells, which are poorly metastatic but form occasional metastases in liver and other organs after long latency. Highly metastatic D2A1 cells provided a positive, metastatic control. Our goals were to learn how the cell lines differ in survival kinetics in a secondary site and to seek evidence for the source of D2.0R dormancy. In spontaneous metastasis assays from mammary fat pad injections, we found evidence for dormancy because of a persistence of large numbers of solitary cells in the liver. To quantify the fate of cells after arrival in liver, experimental metastasis assays were used. To permit identification of cells that had not divided, cells were labeled before injection with fluorescent nanospheres, which were diluted to undetectable levels by cell division. Cancer cells were injected i.v. to target them to the liver and coinjected with reference microspheres to monitor cell survival. Dormancy was defined as retention of nanosphere fluorescence in vivo, as well as negative staining for the proliferation marker Ki67. A large proportion of D2.0R cells persisted as solitary dormant cells. No metastases formed, but viable cells could be recovered from the liver 11 weeks after injection. Large numbers of solitary, dormant, Ki67-negative D2A1 cells were also detected against a background of progressively growing metastases. Thus, this study identified a possible contributor to tumor dormancy: solitary, dormant cells that persist in tissue. If such cells are present in patients, they could contribute to tumor recurrence and would not be susceptible to current therapeutic strategies targeting proliferating cells.

Animals↗
PubMed1987

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↗
PubMed1988

Iron nutrition and tumor growth: decreased tumor growth in iron-deficient mice.

Groups of 15 mice of three different laboratory strains (BALB/c, C3H/He, DBA/2) were fed on a low iron diet (5 mg iron/kg diet), and three similar groups of 15 mice were maintained on a normal iron diet (312 mg iron/kg diet). When the low iron diet group became iron deficient, tumor cells (5 x 10(5) cells/mouse) of CA07-A (colon adenocarcinoma), HE129 (hepatoma), and M119 (mammary adenocarcinoma) were inoculated s.c. in BALB/c, C3H/He, and DBA/2 mice, respectively. All mice developed tumors, tumors grew more slowly, and the mean tumor sizes were smaller in the low iron diet group at nearly all weekly observations in all three strains of mice. No apparent differences in the behavior, activity (e.g., movement, climbing, running, grooming, etc.), and appearance were observed between low iron diet and normal iron diet mice. The mean body weight of mice at transplantation was less in the low iron than in the normal iron groups for the BALB/c strain but higher in the low iron groups of C3H/He and DBA/2 mice, indicating that food intake of mice on a low iron diet was not impaired. These results suggest that iron nutrition of the host affects tumor growth; tumor cells grow better in an iron-rich environment. This knowledge should be considered when designing treatment for patients with cancer. Iron oversupply in cancer patients might enhance tumor growth and adversely affect cancer therapy.

Adenocarcinoma↗
PubMed2003

Initial experience in small animal tumor imaging with a clinical positron emission tomography/computed tomography scanner using 2-[F-18]fluoro-2-deoxy-D-glucose.

The feasibility of small animal imaging using a clinical positron emission tomography/computed tomography (PET/CT) scanner with [F-18]-fluoro-2-deoxy-D-glucose (FDG) was evaluated. As tumor-bearing small animal models, rabbits with VX-2 liver tumors, rats with mammary tumors on the back, and mice with LS174T human colon tumor xenografts were prepared. Two-dimensional PET, CT, and fused PET/CT images were obtained and reconstructed with a combined PET/CT system using a conventional protocol for humans and dedicated high-resolution mode protocols specialized for each species. Estimated radioactivity concentrations in tumors and normal organs determined noninvasively on FDG-PET/CT were compared with the actual tissue radioactivity levels determined from gamma-counting after vivisection in rats. In addition, recovery-corrected radioactivity concentrations were calculated and evaluated using the tumor/normal organ sizes measured on CT. Tumors in rabbits and rats were clearly visualized by FDG-PET/CT in the dedicated protocols, and images were considered suitable for research purposes. With the aid of thin-slice CT-mapping images, FDG uptake was correctly localized in the viable tumor regions. In mice, increased FDG uptake in tumors with varying activity levels was observed, but detailed anatomical information was not optimally provided from the images, even using specialized protocols. The estimated radioactivity concentrations of tumors and normal organs were close to the actual radioactivity concentrations obtained by gamma-counting (r = 0.97, P < 0.001, the estimated/actual slope: 1) when recovery correction was applied using the sample sizes measured on CT. FDG-PET/CT imaging with a modern clinical scanner was demonstrated to be feasible, of excellent quality, and quite quantitatively accurate for research in rabbits or rats with tumors of appropriate size (>2 cm without recovery correction and >1 cm with recovery correction). Evaluation of FDG uptake within a tumor was possible with the aid of CT images. Dedicated small animal PET/CT scanner would be better suited for evaluating tumor-bearing mice and likely could enhance imaging smaller tumors in rabbits or rats. Although it has limitations, small animal imaging with a clinical PET/CT scanner may be quite adequate for sequential noninvasive imaging in oncology research because the CT is of high resolution, allowing for localization of PET findings and for more precise noninvasive estimation of radioactivity concentration through partial volume corrections.

Animals↗
PubMed1987

Effect of heat shock on protein degradation in mammalian cells: involvement of the ubiquitin system.

Exposure of cultured rat hepatoma (HTC) cells to a 43 degrees C heat shock transiently accelerates the degradation of the long-lived fraction of cellular proteins. The rapid phase of proteolysis which lasts approximately 2 h after temperature step-up is followed by a slower phase of proteolysis. During the first 2 h after temperature step-up there is a wave of ubiquitin conjugation to cellular proteins which is accompanied by a fall in ubiquitin and ubiquitinated histone 2A (uH2A) levels. Upon continued incubation at 43 degrees C the levels of ubiquitin conjugates fall with a corresponding increase of ubiquitin and uH2A to initial levels. The burst of protein degradation and ubiquitin conjugation after temperature step-up is not affected by the inhibition of heat shock protein synthesis. Cells of the FM3A ts85 mutant, which have a thermolabile ubiquitin activating enzyme (E1), do not accelerate protein degradation in response to a 43 degrees C heat shock, whereas wild-type FM3A mouse cells do. This observation indicates that the ubiquitin system is involved in the degradation of heat-denatured proteins. Sequential temperature jump experiments show that the extent of proteolysis at temperatures up to 43 degrees C is related to the final temperature and not to the number of steps taken to attain it. Temperature step-up to 45 degrees C causes the inhibition of intracellular proteolysis. We propose the following explanation of the above observations. Heat shock causes the conformational change or denaturation of a subset of proteins stable at normal temperatures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Glucocorticoid receptors.

Glucocorticoid receptors are found in most mammalian tissues and have been studied in detail in a number of tissue culture systems. With cells that have not been exposed to steroids, the receptors are found in the cytoplasmic fraction from which they can be isolated and studied. Methods for studying glucocorticoid receptors depend on their high-affinity specific binding of radioactive steroids. The reversible interaction is intracellular. It follows Michaelian kinetics, at least in cell-free cytosol, and involves a thermodynamically homogeneous population of about 10 000 sites per cell. The receptor is an asymmetric, slightly acidic protein of about 100 000 daltons. It is very labile, especially in the unbound form. Binding activity depends on the integrity of thiol groups and perhaps on phosphorylation of amino acid residues. Although indirect, the evidence is overwhelmingly convincing that this protein is the physiologic glucocorticoid receptor. The time-kinetics of binding and dissociation are consistent with the sequence of events in glucocorticoid action. Various steroid analogs display binding characteristics predictable from their glucocorticoid activity. Loss of the binding protein from certain cultured cell lines is accompanied by unresponsiveness to glucocorticoids. The extensive tissue distribution of receptors parallels the extensive role of glucocorticoids in regulation. Finally, there is a strong correlation between nuclear binding of receptors and nuclear effects of the steroid. The glucocorticoid receptor can be distinguished from other glucocorticoid-binding proteins, based on their steroid specificity and physicochemical properties. There is no clear-cut demonstration that the receptor differs from tissue to tissue, and it is in fact very similar in various species. Unlike in other systems, receptor concentration does not seem to be regulated by its ligand or by other hormones. However, certain cases of hypo- as well as hypersensitivity to glucocorticoids appear to result from changes at the receptor level. The data indicate that the receptor can exist in inactive and active forms. The former predominate in the absence of steroid or when an angatonist is bound. Glucocorticoid agonists bind the active form, allowing it to be "activated" and subsequently bound to the nucleus. All of the receptors in isolated cytosol do not appear to be available for immediate occupancy by an agonist and this may be due to the time required for conversion of the receptors from inactive to active forms. The correlations between receptor binding and the glucocorticoid response indicate that the receptor is a rate-limiting factor in the magnitude and kinetics of the response, and this finding has important implications regarding mechanisms.

Animals↗