Tumors In Syrian Hamsters Research Articles

Prostaglandin E(2) release by human and Syrian hamster tumor cells and their sensitivity to cytostatic activity of natural killers.

The release of prostaglandin E(2) by human and Syrian hamster tumor cells in response to contact with natural killers and their sensitivity to cytostatic activity of natural killers were studied. A previously reported correlation between prostaglandin E(2) release by Syrian hamster tumor cells and their resistance to cytostatic activity of natural killers was confirmed. This resistance can be cancelled by inhibition of prostaglandin E(2) release with indomethacin. Unlike malignant tumor cells of Syrian hamsters, only few human tumor cells resistant to cytostatic activity of natural killers secrete prostaglandin E(2). The resistance of these cell strains to cytostatic activity of natural killers could be cancelled by indomethacin treatment. Possible role of prostaglandin E(2) release as a mechanism of tumor cell protection from effector cells of this type of natural (congenital) immunity is discussed.

Demonstration of estrogen receptors and of estrogen responsiveness in the HKT-1097 cell line derived from diethylstilbestrol-induced kidney tumors.

This study was undertaken in order to examine the estrogen sensitivity of HKT-1097, an established cell line recently derived from diethylstilbestrol (DES)-induced kidney tumors in Syrian hamsters. Estrogen receptor (ER) level in HKT-1097, determined by enzyme-linked immunoassay, was 67 fmol/mg protein, i.e., a value approx. 30% lower than that found in Syrian hamster kidney tumors. ER immunostaining in cells fixed with Carnoy's mixture, as well as ER demonstration by Western blotting, suggested DES-induced nuclear translocation or stabilization of the receptor within the nucleus. Kinetic parameters of estrogen binding to ER in HKT-1097 cells were 8.4 x 10(-11) M and 60.8 fmol/mg protein for Kd and Bmax, respectively. The Kd of estrogen binding to ER in HKT-1097 was close to that evaluated for the receptor in breast cancer-derived MCF-7 cell line, whereas the Bmax value was approx. seven times lower in HKT-1097 as compared to MCF-7. In HKT-1097 cells, antiestrogens ICI 182,780 and RU 58,668 induced ER downregulation and competed with estrogen binding to the receptor. As demonstrated by Western blot analysis, DES exposure led to an increased expression of progesterone receptor (PgR) in HKT-1097 cells. Addition of DES to estrogen-free medium produced a stimulation of growth in both HKT-1097 and MCF-7 cells, but the mitogenic effect was less marked for HKT-1097. Despite the fact that ICI 182,780 and RU 58,668 clearly interact with HKT-1097 cell ER, they appeared unable to suppress DES-induced stimulation of growth and increase of PgR expression.

Early changes in islet hormone secretion in the hamster pancreatic cancer model

The diabetic state that is seen at a high frequency in association with pancreatic cancer is characterized by elevated plasma levels of several islet hormones and by marked insulin resistance. Both the diabetic state and insulin sensitivity improve after tumor removal by sub-total pancreatectomy. Impaired glucose tolerance has also been found in the hamster pancreatic cancer model, but conflicting data regarding islet function have been reported. In order to further investigate islet function and secretion during early development of pancreatic cancer, we measured the concentrations of insulin, glucagon, somatostatin, and islet amyloid polypeptide (IAPP) in plasma, pancreatic tissue, and secretin-stimulated pancreatic juice at 12 and 27 weeks after the ductal-cell-specific carcinogen, BOP had been used to induce tumors in Syrian golden hamsters. At 12 weeks after BOP, plasma glucagon levels were significantly increased. An exaggerated plasma-glucose response and concomitant hyperinsulinemia were observed at 27 but not 12 weeks after BOP. Plasma IAPP concentrations, but not glucagon or somatostatin, were elevated at 27 weeks. Tissue concentrations of IAPP were substantially reduced in BOP-treated hamsters at 27 weeks. No differences in hormone concentrations were seen in pancreatic juice from the two groups at either of the two time points investigated. The study showed that islet hormone changes accompany the early development of pancreatic tumors in the hamster pancreatic model. The hormone changes and apparent insulin resistance resemble the metabolic changes found in humans with pancreatic cancer.

Characterization of a cell line established from diethylstilbestrol-induced renal tumors in Syrian hamsters.

This article describes HKT-1097, a new cell line established from renal tumors induced by the protracted administration of diethylstilbestrol (DES) to male Syrian golden hamsters. Cell culture was initiated from tumor samples obtained from two 14-mo.-old animals which had undergone exposure to DES for a period of 11 mo. The HKT-1097 cell line was characterized between Passages 16 and 22 with respect to cell morphology, growth properties, karyology, and the presence of estrogen receptors. Moreover, immunostaining with a panel of antisera was performed to identify the cytological profile of the cell line and establish a parallel with tumor tissue in vivo. HKT-1097 cells are fibroblastoid; their most distinctive feature is that they exhibit strikingly long processes. The HKT-1097 cell line grows as a monolayer with a tendency toward a less stringent density-dependent inhibition of growth. The modal chromosome number is 44, but more than 50% of the cells are aneuploid, suggesting a substantial degree of karyotype instability. HKT-1097 cells express estrogen receptors. They contain immunoreactive vimentin and desmin, but appear negative upon cytokeratin immunostaining. In addition, these cells express glial fibrillary acidic protein and other markers of the neuroectodermal lineage, but lack neurofilament protein. Insofar as the same lineage markers have been demonstrated in DES-induced Syrian hamster kidney tumors (SHKT), we conclude that HKT-1097 cells retain some of the original tumor cell phenotype. The current observations suggest that estrogen-induced SHKT derive from the renal interstitium and point to an involvement of neuroectodermal cells in the development of these neoplasms.

Differential regulation of c-fos expression in estrogen-induced hamster renal tumors compared with kidney not due to creation of an estrogen-response element by point mutation in the gene's flanking sequence

The conversion of a palindromic sequence, GGTCTnnnAGACC, in the 5'-flanking region of the murine c-fos proto-oncogene into a functional estrogen-response element by a single base change into GGTC(A/G)nnnAGACC has previously been postulated [Nawaz et al., 1993] as a possible mechanism of the induction of tumors by estrogens. This attractive hypothesis has been investigated in estradiol-induced Syrian hamster kidneytumors, in H-301 kidney tumor cells (a cell line derived from the Syrian hamster tumor), and in normal kidney tissue. The c-fos gene is differentially regulated by a classical estrogen receptor-mediated process in tumors, whereas in the acutely treated kidney, estradiol induces c-fos expression independent of estrogen-receptor function. In this study, we identified in the 5'-flanking region of the hamster kidney c-fos gene the sequence AGTCCnnnAGACC, which closely resembled but did not appear to function as an estrogen-response element. No mutations were detected in this sequence or in the 5'-flanking region of c-fos genes from three different primary tumors and from H-301 tumor cells. To rule out the possibility of a low copy number of mutant alleles in a tumor sample, polymerase chain reaction-based single-strand conformation polymorphism analysis was performed on 372 base pairs of the 5'-flank of the c-fos gene (-367 to +5 base pairs relative to the transcription start point). Nine different kidney tumor DNA samples and five normal kidney tissue samples (controls) produced an identical pattern of DNA bands, suggesting a lack of natural polymorphisms and mutations in this region of the c-fos gene. Acute treatment of hamsters with 17beta-estradiol for 6 h significantly induced renal c-fos mRNA expression, whereas control levels of c-fos were restored by co-treatment with estradiol and either N-acetyl-L-cysteine or alpha-naphthoflavone. We concluded that the previously observed change in regulatory control of c-fos expression in kidney versus estradiol-induced tumors does not involve the creation of a functional estrogen-response element by single point mutation in the 5'-flanking region of the gene. Additionally, c-fos expression in estradiol-treated hamster kidneys appears to be mediated by free radicals generated by the catechol metabolites of estradiol and not by the activation of any estrogen receptor.

SCREENING METHOD FOR URINARY BLADDER TUMOR DETECTION IN THE SYRIAN HAMSTER

A screening method is described for the detection of urinary bladder tumors in Syrian hamsters. The urinary bladder is removed, stained with 0.2% methylene blue in sodium phosphate buffer, pinned out flat, and fixed for 1 h in 4% paraformaldehyde in sodium phosphate buffer. The urinary bladder is examined with a dissecting microscope for the presence of stained and/or irregular areas and nodules, which are subjected to histological analysis. The screening method may reduce the possibility of missing small lesions with regular gross examination or the need to examine over 100 slides per animal.

Resistance of spontaneously transformed Syrian hamster embryo cells and their malignant variants to cytotoxic activity of recombinant tumor necrosis factor-alpha.

To study the possible role of the host macrophages in the selection of tumor cells and tumor progression, a series of Syrian hamster tumor cell lines all originating from a single spontaneously transformed Syrian hamster embryo cell line (STHE strain) have been established. These STHE tumor cell variants, selected either in vitro with resident and lipopolysaccharide-activated macrophages or in vivo, differ in tumorigenic and metastatic activity. The selected malignant STHE cells become resistant to cytotoxic activity of activated peritoneal macrophages and of exogenous hydrogen peroxide (H2O2). Since activated macrophages are a known source for both cytotoxic agents H2O2 and tumor necrosis factor (TNF), the purpose of the present study was to define the sensitivity of the STHE tumor cell lines to a direct cytotoxic activity mediated by recombinant TNF-alpha in an attempt to understand the role of the cytokine in in vitro selection of a malignant STHE cells by activated macrophages. The spontaneously transformed STHE cells (selected in vivo and in vitro) as well as the hamster embryo cells transformed in vitro by a tumorigenic Rous sarcoma virus (Schmidt-Ruppin strain) were used as targets. TNF-alpha-sensitive mouse L929 cells were included in the study as a positive control. Sensitivity of actinomycin D-pretreated target cells studied for cytotoxic activity of a recombinant TNF-alpha was examined over 21 h with a crystal violet dye assay. It was found that, in contrast to L929 cells, the spontaneously transformed STHE cells as well as tumorigenic Rous sarcoma virus hamster embryo transformants, were all significantly resistant to the TNF-alpha-mediated cytolysis. This indicates that TNF-alpha is not the single factor responsible in in vitro selection of malignant STHE cell variants by activated macrophages. It appears that H2O2 is involved in the selection of the hamster macrophage-resistant STHE tumor cells.

Cytochrome P450 Metabolism of Estradiol in Hamster Liver and Kidney

Estradiol induces kidney tumors in Syrian hamsters. The elevated conversion of estradiol to 4-hydroxylated metabolites in kidney compared to the predominant 2-hydroxylation in liver and other organs, where tumors are not induced by this treatment, has been proposed to be the basis of estrogen-induced carcinogenesis. In this study, we examined the hepatic and renal enzymes catalyzing the formation of catecholestrogens to understand the differences in estrogen metabolism in these organs. In liver, 2-hydroxylation of estradiol is the major metabolic pathway with 4-hydroxylation a minor by-product and with the formation of both catechols responding coordinately to the same inhibitors. Western blot analysis and inhibition studies suggest that the major form catalyzing hepatic estrogen 2-hydroxylation is a member of the CYP3A family, as previously observed with rat liver microsomes, and that 4-hydroxylation is a by-product of this metabolism. In the kidney, 4-hydroxylation of estradiol appears to be catalyzed by more than one enzyme according to the Eadie–Hofstee analysis. Both 2- and 4-hydroxylation in the kidney are affected differentially by inhibitors and are induced by β-napthoflavone. Western blots of renal microsomes reveal that CYP1A2 is induced whereas CYP1A1 is detectable in kidney, but not induced by this treatment. Finally, a part of the 2-hydroxylation and a small part of the 4-hydroxylation by kidney microsomes may be catalyzed by a member of the CYP3A family, since these reactions are partially inhibited by CYP3A inhibitors such as progesterone and other progestins, although renal enzyme levels are much lower than those in the liver as revealed by Western blot. Our data suggest that estrogen 2-hydroxylation in the hamster kidney is catalyzed by members of the CYP1A and CYP3A families, which also contribute to 4-hydroxylation. The majority of 4-hydroxyestradiol formation in the hamster kidney may be catalyzed by a form(s) of the newly discovered CYP1B family that has yet to be characterized.

Lung Tissue Responses and Sites of Particle Retention Differ between Rats and Cynomolgus Monkeys Exposed Chronically to Diesel Exhaust and Coal Dust

Several chronic inhalation bioassays of poorly soluble, nonfibrous particles have resulted in an increased incidence of lung tumors in rats, no increase in lung tumors in Syrian hamsters, and inconsistent results in mice. These results have raised concerns that rats may be more prone than other species to develop persistent pulmonary epithelial hyperplasia, metaplasia, and tumors in response to the accumulation of inhaled particles. In addition, particle deposition and the rate of particle clearance from the lung differ between rats and primates, as does the anatomy of the centriacinar region. For these reasons, the usefulness of pulmonary carcinogenicity data from rats exposed to high concentrations of particles for quantitatively predicting lung cancer risk in humans exposed to much lower environmental or occupational concentrations has been questioned. The purpose of this investigation was to directly compare the anatomical patterns of particle retention and the lung tissue responses of rats and monkeys exposed chronically to high occupational concentrations of poorly soluble particles. Lung sections from male cynomolgus monkeys and F344 rats exposed 7 hr/day, 5 days/week for 24 months to filtered ambient air, diesel exhaust (2 mg soot/m3), coal dust (2 mg respirable particulate material/m3), or diesel exhaust and coal dust combined (1 mg soot and 1 mg respirable coal dust/m3) were examined histopathologically. The relative volume density of particulate material and the volume percentage of the total particulate material in defined pulmonary compartments were determined morphometrically to assess the relative amount and the anatomic distribution of retained particulate material. In all groups, relatively more particulate material was retained in monkey than in rat lungs. After adjustment for differences between rat and monkey controls, the coal dust- and the combined diesel exhaust and coal dustexposed monkeys retained more particulate material than the coal dust- and the combined diesel exhaust and coal dust-exposed rats, respectively. There was no significant difference in the relative amount of retained particulate material between diesel exhaustexposed monkeys and rats. Within each species, the sites of particle retention and lung tissue responses were the same for diesel soot, coal dust, and the combined material. Rats retained a greater portion of the particulate material in lumens of alveolar ducts and alveoli than monkeys. Conversely, monkeys retained a greater portion of the particulate material in the interstitium than rats. Rats, but not monkeys, had significant alveolar epithelial hyperplastic, inflammatory, and septal fibrotic responses to the retained particles. These results suggest that intrapulmonary particle retention patterns and tissue reactions in rats may not be predictive of retention patterns and tissue responses in primates exposed to poorly soluble particles at concentrations representing high occupational exposures.

Intracranial tumours in Syrian golden hamsters

Intracranial tumours in Syrian golden hamsters

Adjuvant chemoprevention of experimental cancer: catechin and dietary turmeric in forestomach and oral cancer models

Catechin and dietary turmeric ( Curcuma longa) were used as chemopreventive agents in benzo[ a]pyrene induced forestomach tumors in Swiss mice and methyl-(acetoxymethyl)-nitrosamine induced oral mucosal tumors in Syrian golden hamsters. Catechin in drinking water and dietary turmeric significantly inhibited the tumor burden and tumor incidence in both tumor models. The induction of oral tumors in golden hamsters was delayed by catechin and dietary turmeric. Adjuvant chemoprevention utilising both catechin and dietary turmeric inhibited both the gross tumor yield and burden more effectively than when compared to individual components in both tumor models. A single i.p. injection of catechin to male Swiss mice induced increased forestomach and hepatic glutathione S-transferase (GST) activity when compared to controls. These findings suggest that catechin and turmeric which are regularly consumed natural products, are effective in mice or golden hamsters as chemopreventive agents.

Frequency of metastasis in Syrian hamster tumor cells selected for low levels of “typical” multidrug resistance

The metastatic capability of cells at the initial stages of selection for "typical" (P-glycoprotein-mediated) multidrug resistance (MDR) was studied. Two independent sublines, 2SC/4-1 and 2SC/4-2 (11-12.4-fold resistant), and their 23- to 23.7-fold resistant 2SC/20-1 and 2SC/20-2 variants were isolated from highly tumorigenic (TrD50 = 10 cells) and highly metastatic Rous sarcoma, virus-transformed Syrian hamster fibroblast HET-SR-2SC-LNM line for resistance to colchicine. 2SC/4 cells were less tumorigenic (TrD50 = 70 cells) but as highly metastatic as parental counterparts. In contrast, both 2SC/20 variants showed a decrease in tumorigenicity (TrD50 = 320 cells) and in the capability to produce spontaneous distant metastases. 2SC/20 cells almost lost the ability to colonize lungs in experimental metastasis assay. The autophosphorylation of pp60src tyrosine kinase in 2SC/20 cells was unaltered. The results suggest that i) selection of tumor cells for low levels of "typical" MDR leads to a decrease in the frequency of spontaneous and experimental metastases, and ii) alterations of malignancy in these cells are not caused by an impairment of function of a transforming oncogene.

Effect of acute administration of N-nitrosopyrrolidine to male Syrian golden hamsters.

A protocol has been developed which decreases the time for administration of N-nitrosopyrrolidine (NPYR) to male Syrian golden hamsters from 25 weeks to a single i.p. injection. Animals were divided into five groups: group I received two 0.5-mmol doses on alternate days; group II was given three 0.33-mmol doses on alternate days; group III received a single dose of 0.5 mmol; group IV was given a single dose of 0.25 mmol and group V served as a control and received saline. Preneoplastic and neoplastic changes in the upper respiratory tract and liver were observed in all carcinogen-treated groups. The number of animals with laryngeal and tracheal tumors in the NPYR-treated groups was dose-dependent. Groups I and II, respectively, had 21 of 26 (81%) and 18 of 24 (75%) animals with either laryngeal or tracheal tumors. Groups III and IV showed 4 of 12 (33%) and 3 of 13 (23%) hamsters with these tumors. No laryngeal or tracheal tumors were observed in control animals. These results indicate that a single dose of NPYR is sufficient to induce respiratory tract tumors in Syrian golden hamsters.

The carcinogenic activity of ethinyl estrogens is determined by both their hormonal characteristics and their conversion to catechol metabolites.

Estrogens induce kidney tumors in Syrian hamsters. The mechanism of carcinogenesis is unknown and has been investigated in this study using a weak carcinogen, 17 alpha-ethinyl estradiol (EE), and a strongly carcinogenic estrogen, 17 alpha-ethinyl-11 beta-methoxyestradiol [moxestrol (MOX)]. We investigated rates of conversion of estrogens to catechol metabolites and rates of their methylation to methyl ethers in order to examine the hypothesis that catechol metabolites mediate estrogen-induced carcinogenesis. Rates of conversion of MOX to catechol metabolites by hamster liver or kidney cortex microsomes were 40-50% of those with estradiol as substrate. However, the rate of catechol-O-methyltransferase-catalyzed methylation of 2-hydroxy-MOX was the least of the catechol metabolites examined when incubated with cytosol of hamster kidney. In contrast, EE was converted to catechol metabolites by hamster liver and kidney microsomes at rates 25-35% of those obtained with estradiol. These catechol metabolites of EE were methylated by catechol-O-methyltransferase of hamster kidney cytosol at rates slightly lower than those observed with catechols of estradiol. The progesterone receptor binding of EE and MOX was investigated, because progesterone is known to inhibit estrogen-induced carcinogenesis in the hamster kidney. Neither estradiol nor MOX inhibited the binding of progesterone to its receptor in hamster kidney cytosol. However, in the presence of 20 nM EE, the binding affinity of radiolabeled progesterone to receptor was inhibited (increase in Kd from 0.98 nM in controls to 3.02 nM in the presence of EE). Maximum binding values (5.0 fmol/mg protein in controls and 6.0 fmol/mg protein in the presence of EE) were not significantly altered. These results support the hypothesis that estrogen-induced carcinogenesis is mediated by catechol estrogen metabolites. The carcinogenic estrogen MOX is converted to catechol metabolites at lower rates than estradiol, but their methylation may be sterically hindered by the 11 beta-methoxy substituent. In contrast, the rates of conversion of the weakly carcinogenic EE to catechol metabolites are low, whereas their methylation rates are only marginally lower than those of 2- and 4-hydroxyestradiol. The decreased capacity of EE to form catechol metabolites in conjunction with its partial progestin agonist activity in the target organ of hamsters may contribute to the low tumor incidence.

Papovavirus-induced trichogenous tumours in Syrian hamsters (Mesocricetus auratus).

Tumorous, virus-induced skin lesions in two golden hamsters (Mesocricetus auratus) were characterized macroscopically and by means of light- and electron-microscopy. Evidence of a virus was demonstrated in the ultra-thin sections and by the negative staining method. The morphological findings confirm the assumption that infections with papoviruses--probably of the polyomavirus genus--were involved.

Lack of effectiveness of antiestrogens RU 39,411 or keoxifene in the prevention of estrogen-induced tumors in Syrian hamsters

As part of a search for an effective and safe antiestrogen to be used as adjunct therapy in the treatment of breast cancer, we examined the potential of RU 39,411 and keoxifene to inhibit the incidence of estradiol-induced kidney tumors in Syrian hamsters. Groups of 10 hamsters were chronically treated with implants of either keoxifene, RU 39,411, estradiol plus keoxifene, or estradiol plus RU 39,411 for 8 months. Five hamsters received only estradiol and 5 control animals remained untreated. There was a 100% kidney tumor incidence in estradiol-treated hamsters, which was not statistically different from that in animals co-treated with estradiol plus keoxifene (3 of 4 hamsters with tumors) or estradiol plus RU 39,411 (7 of 8 hamsters with tumors). Rodents treated only with antiestrogen remained tumor free. In addition to kidney tumors, testicular cancer was also found in animals cotreated with either estradiol plus keoxifene (2 of 4 hamsters with tumors) or estradiol plus RU 39,411 (3 of 8 hamsters with tumors). Two animals of this latter group also developed liver tumors. Testicular or liver neoplasms were not observed in hamsters implanted only with estradiol or only with antiestrogen. The lack of inhibition of estrogen-induced carcinogenesis in hamsters by RU 39,411 or keoxifene suggests that these two antiestrogens are not as effective as previously tested substances in inhibiting the appearance of this cancer. However, their concentrations were sufficient to induce, in combination with estradiol, the development of testicular tumors in these hamsters.

Elevation of protooncogene messenger RNAs in estrogen-induced kidney tumors in the hamster.

Cellular oncogenes such as c-fos, c-jun and c-myc are expressed prior to estrogen-induced growth of normal target tissues such as rodent uterus. Transient increases in the levels of these genes are induced by the administration of estradiol and are followed by DNA replication. In this study, we examined the expression of these three oncogenes in estradiol-induced kidney tumors in Syrian hamsters in order to understand mechanistic aspects of hormonal carcinogenesis. Kidney tumors were induced in all male Syrian hamsters treated chronically with estradiol for 7 or 9 months, whereas neoplasms were not detected in animals treated for 5 months. mRNA levels of fos, myc and jun were elevated 15-, 4- and 6-fold respectively in kidney tumors of estradiol-treated hamsters (9 months) compared with age-matched untreated control kidneys. The expression of all three protooncogenes was also increased in the kidney tissue surrounding tumors, though there was no consistent pattern in the ratios of transcripts in the tumor and kidney tissues. After 7 months of estrogen treatment, kidney tumors also contained elevated amounts of c-fos, c-jun and c-myc transcripts at levels comparable with older tumors. In abdominal metastases of hamster kidney tumors, mRNA levels of fos, myc and jun were elevated 9-, 12- and 3-fold respectively over control levels. In kidneys of hamsters treated with estradiol for 5 months, in which tumors were not yet detected, the expression of protooncogenes was slightly increased. Ratios of c-fos, c-myc and c-jun in estrogen-treated (5 months) over control tissue were 1.4, 1.1 and 1.3 respectively. Overexpression of cellular oncogenes such as c-fos, c-jun and c-myc may have played a role in the induction and growth of kidney tumors by estradiol in hamsters.

Changes in the cellular phenotype and extracellular matrix during progression of estrogen-induced mesenchymal kidney tumors in Syrian hamsters

The cellular origin of estrogen-induced kidney tumors in male Syrian hamsters has been repeatedly the subject of controversy. Several authors have proposed that the tumors arise from proximal tubules, from a combination of tubular and interstitial stromal cells, or solely from interstitial cells. Because of the model character of this tumor for hormone-associated cancer, it was further investigated in this study with respect to morphology, enzyme and intermediate filament pattern, the expression of alpha-smooth muscle actin and the extracellular matrix proteins fibronectin and tenascin. These analyses were carried out with early and late tumors as well as metastases to determine possible changes in expression of biochemical parameters during the development and progression of this neoplasm. The enzyme histochemical and intermediate filament patterns were usually the same as those described previously for proliferative foci and early tumors, i.e. highly elevated activities of glucose-6-phosphate dehydrogenase, adenylate cyclase and alkaline phosphatase, a lack of glucose-6-phosphatase and gamma-glutamyltransferase and coexpression of vimentin and desmin, alpha-smooth muscle actin could not be detected in early lesions. In five of 24 advanced tumors inclusions of kidney tubules were found which showed various degrees of alteration in their morphology and enzyme histochemical pattern, but were often directly connected with tubular segments of normal appearance outside the tumor. Like the normal tubules, the enclosed tubular segments were strongly positive for cytokeratin but never expressed vimentin or desmin. Among the 24 tumors studied, two contained cysts which expressed cytokeratin and sometimes also vimentin but not desmin. The enzyme histochemistry of the cells lining the cysts was similar to that of the surrounding tumor mass, except adenylate cyclase was lacking and alkaline phosphatase was not uniformly distributed. In tumors containing cytokeratin-positive cysts, there often were cytokeratin-positive, vimentin-negative and desmin-negative tumor formations in close contact to these cysts. With the exception of cyst formation, the pattern of metastases were identical to that of the primary tumors. All large tumors and the main component of the metastases expressed vimentin, desmin and fibronectin. Mesothelia surrounding metastatic tumor complexes were positive for vimentin, desmin, alpha-smooth muscle actin, fibronectin, cytokeratin and tenascin. It was concluded from these and previous observations on early stages of tumor development that the estrogen-induced hamster kidney tumor originates from mesenchymal interstitial cells (probably pericytes) which may rarely acquire an epithelial phenotype by metaplastic transformation during tumor progression.

Prostatic atrophy in dogs after intravenous administration of a ureido-ethylimidazoline derivative (CGP15′720A)

1-(2-[4-Pridyl)-2-imidazoline-1-yl]-ethyl)-3-(4-carboxyphenyl)urea (CGP15'720A) is an experimental antineoplastic agent with marked activity against carcinogen-induced lung tumors in Syrian hamsters and human lung tumor xenografts in nude mice. A preclinical toxicity study of this agent was carried out in mice and dogs which demonstrated the relatively nontoxic nature of the agent. In mice, single intraperitoneal dosage of 12 g/m2 did not produce lethality; however, lethality (30% of treated mice) was seen during treatment with 6 g/m2 daily for 5 days. No hematological, serum-chemistry or histopathological changes were detected in mice after single or five consecutive treatments with 12 g/m2. Dogs were treated with doses ranging from 5 g/m2 to 80 g/m2, with deaths occurring in a non-dose-related fashion after 10, 20, and 40 g/m2. Acute neurological toxicity after infusion was the dose-limiting toxicity in dogs. There were no consistent hematological or serum-chemistry aberrations in the treated dogs. The most consistent histopathological finding was prostatic atrophy, which was detected in 5/12 dogs in this series.

Identification and characterization of the hamster polyomavirus middle T antigen

Hamster polyomavirus (HaPV) is associated with lymphoid and hair follicle tumors in Syrian hamsters. The early region of HaPV has the potential to encode three polypeptides (which are related to the mouse polyomavirus early proteins) and can transform fibroblasts in vitro. We identified the HaPV middle T antigen (HamT) as a 45-kDa protein. Like its murine counterpart, HamT was associated with serine/threonine phosphatase, phosphatidylinositol-3 kinase, and protein tyrosine kinase activities. However, whereas mouse middle T antigen associates predominantly with pp60c-src and pp62c-yes, HamT was associated with a different tyrosine kinase, p59fyn. The ability of HaPV to cause lymphoid tumors may therefore reside in its ability to associate with p59fyn, a potentially important tyrosine kinase in lymphocytes.