bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Succinate on Amino Acid Incorporation into Protein during Chemical Carcinogenesis
Authors: Fonnesu Alberto , Capaccioli Sergio , Cini-Neri Grazia
Published: September 2009

The starting point of this study is the observation that succinate, the well-known Krebs cycle intermediate, strongly inhibits the incorporation of amino acids into protein of tissue slices. The results presented in this paper show that this somewhat peculiar succinate effect, which is present in regenerating liver and in a well-differentiated hepatoma and absent in two anaplastic hepatomas, is well-marked in all stages of hepatic carcinogenesis by N, N'-dimethyl-4-aminoazobenzene. A working hypothesis is that the inhibition by succinate of the amino acid incorporation into protein is mediated by a shift of the redox level in the cell toward a more reduced condition.
Inhibition of DNA and RNA Synthesis in Rat Liver Nuclei by Oncogenic and Non-oncogenic β-Blockers
Authors: Riboni Laura , Presta Marco , Ziliani Silvia , Mazzocchi Cecilia , Braga Giovanni , Mazzoleni Giovanna , Ragnotti Giovanni
Published: September 2009

The β-blocker DL-1-(2-nitro-3-methylphenoxy)-3- tert-butylaminopropan-2-ol (ZAMI 1305), hepatocarcinogenic to the female rat, and the non-oncogenic β-blockers DL-1-(2-nitro-5-methylphenoxy)-3- tert-butylaminopropan-2-ol (ZAMI 1327), DL-propranolol, and DL-atenolol were studied for their capacity to interfere with hepatic DNA and RNA synthesis. These moieties inhibit DNA and RNA synthesis, in a dose-dependent fashion, when added in vitro to nuclei isolated from the liver of male or female rats. The inhibition is due to a decrease of the initial rate of synthesis and of the total amount of labeled precursor incorporated into the growing chains. When administered in vivo both the oncogenic ZAMI 1305 and its non-oncogenic isomer ZAMI 1327 inhibit hepatic DNA and RNA synthesis in female rats, as evaluated by the determination of nucleic acids synthesis in liver nuclei isolated from female rats 5 and 15 min after the injection of the drug. No influence on hepatic DNA and RNA synthesis is observed when the molecules are administered to male rats. The in vivo administration of DL-propranolol causes an increase of hepatic DNA and RNA synthesis in male rats, while it is uneffective in female rats.
Effects of the Irreversible Ornithine Decarboxylase Inhibitor, α-Difluoromethylornithine, Aflatoxin B1, and Choline Deficiency on Hepatocarcinogenesis
Authors: Sondergaard Dorrit , Taylor Francee , Newberne Paul M.
Published: September 2009

Liver carcinogenesis was induced in rats by aflatoxin B1 (AFB1) enhanced by a choline-deficient diet. In Experiment 1, the ornithine decarboxylase inhibitor, α-difluoromethylornithine (DFMO), was administered by gavage to one group only during AFB1 administration; another group received DFMO during AFB1 administration and for 2 months after carcinogen administration. These two groups were compared to two control groups, one given AFB1 and fed the choline-deficient diet and another fed the deficient diet only. In a second experiment, DFMO was administered at a concentration of 2% in the water for 3 weeks and then at 1% for the remainder of the study. Rats from each group in Experiment 1 were killed at 2, 8, and 10 months after AFB1 administration and the development of tumors was followed by histology; autoradiography of [3H]thymidine incorporation into DNA; enzyme histochemistry; and α-fetoprotein determination. The group given DFMO during AFB1 administration was not significantly different from the AFB1-treated control group at 2 and 8 months after AFB1 administration. However, at 10 months following AFB1 and DFMO administration, the [3H]thymidine-labeling index and glucose-6-phosphatase staining were significantly increased. This group had three animals bearing hepatocellular carcinomas as compared to none in the controls. The group given DFMO for 2 months after AFB1 administration had a significantly depressed growth rate 2 months later, but this difference was not apparent after 8 months. After 10 months, there was a significantly increased [3H] thymidine-labeling index and increased volume fraction of γ-glutamyltranspeptidase in the AFB1-DFMO-treated group as compared to the controls. DFMO appeared to inhibit growth under some conditions, but if administration was discontinued after AFB1 exposure, it appeared to enhance tumorigenesis. In Experiment 2, where a larger dose of AFB1 was used and DFMO was administered in the water from start to finish of the experiment, DFMO inhibited tumor induction and depressed the appearance of markers examined during carcinogenesis. These data indicate that the regimen used for DFMO administration can markedly affect tumor induction.
Prognostic Role of Cell Morphology of Animal Tumors
Authors: Koestner Adalbert
Published: September 2009

The purpose of this presentation is to determine the prognostic role of cellular morphology in animal neoplasia. With some exceptions, cellular morphology is the single most accurate predictor of the prospective behavior of neoplasms. There is generally a positive correlation between the degree of malignancy and prognosis. The exceptions are a) morphologically malignant-appearing tumors following a benign course (e.g., canine histiocytoma, canine seminoma, equine sarcoid) and b) morphologically differentiated tumors exhibiting an unpredictable prognosis (e.g., canine pericytoma, acanthomatous epulis, myxoma, follicular thyroid cell carcinoma, etc.). Anaplasia, an important characteristic of most malignant neoplasms, may be less stable than generally assumed. Sodium butyrate may reverse it intermittently and anaplastic gliomas may loose all morphologic and cytokinetic characteristics of anaplasia following sodium butyrate exposure. Host factors, such as nerve growth factor, have similar and more lasting effects upon anaplastic cells derived from the neural crest. Such factors may act as reverse transformation agents and may represent prospective therapeutic agents for anaplastic tumors.
Profiles of Induced Tumors in Animals
Authors: Bucci Thomas J.
Published: September 2009

Chemical carcinogens often induce neoplasms which differ qualitatively and quantitatively from tumors that occur spontaneously in the tissue of interest. While some experimental models have produced neoplasms indistinguishable from their spontaneous counterparts, most cause growths that are histogenetically or morphologically different, larger, more numerous, more aggressive, or of shorter latency. Induced tumors may occur in tissues where spontaneous tumors are uncommon. Cells of induced tumors may express phenotypic characteristics (e.g., membrane antigens) not present in corresponding nonneoplastic or spontaneously neoplastic cells. Conversely, some characteristics present in normal or spontaneously neoplastic cells (e.g., certain enzyme activity) may be absent in induced neoplasms. Not only may carcinogens induce tumors that differ from spontaneous ones, but the effect or a particular carcinogen may vary with the condition of its use. The species of strain, sex, and age of the host as well as the dose and route of administration are major variables. Neoplasia is one result of altered cell regulation. If we postulate a central dogma for oncogenensis, induced tumors should arise from the same molecular mechanisms that produce spontaneous tumors. Differences in “profile” reside not in the ultimate mechanism, but in the events which surround it. They result from the myriad of factors which determine the dose of proximal carcinogen to the cell's sensitive volume, together with those that modify subsequent proliferation and differentiation.
How Does Japan Differentiate Hyperplasia from Neoplasia?
Authors: Enomoto Makoto
Published: September 2009

A Japanese pathologist's contribution to the discussion of the problem on differentiation of hyperplasia from neoplasia is to introduce his experience and knowledge in human and experimental pathology of gastric, hepatic, and uterine cervical cancers, all of which are prevalent in Japan. Canine and rodent gastric cancers induced experimentally by N-ethyl- N′-nitro- N-nitrosoguanidine or N-methyl- N′-nitro- N-nitrosoguanidine, respectively, show different histologic types which are similar to human gastric cancer when examined routinely by endoscopic method. Dogs show more similarities to human gastric cancer than rats in the morphologic features and responses to chemotherapy. Serial liver biopsies performed on patients with fiver diseases revealed the final stages of liver cell carcinoma in some of them. They all progressed to liver cirrhosis before terminating in carcinoma. However, this does not mean that the hyperplastic nodule is an obligatory precursor of carcinoma in human. Among experimental models of liver cancer produced by a large number of agents, only carbon tetrachloride and luteoskyrin seem to induce liver cell carcinoma combined with cirrhotic lesions in rodents. The mode of manifestation of atypical changes in the proliferating cells as preneoplastic or neoplastic lesions seems to differ according to tissue. The cellular pathology of cervicovaginal smears is a reliable index for detection of carcinoma in the cervix, where the appearance of atypical cells represents a landmark between benign and malignant tumors.
Dose Relationships in Experimental Carcinogenesis: Dependence on Multiple Factors Including Biotransformation
Authors: Clayson David B.
Published: September 2009

The probability of obtaining a tumor in a carcinogenesis bioassay depends mainly on the time on test and on the dose of carcinogen used. There is very limited data on the shape of this surface or reliable data on dose-response or time on test-response relationships. Ullrich's data on tumor induction by low dose radiation shows a variety of shapes of curve depending on the tissue chosen for investigation. As radiation probably does not concern the processes involved in xenobiotic metabolism, these observations clearly demonstrate that factors other than metabolism are important. An attempt is made to discuss the shape of the dose-response curve in relation to a number of factors including the background incidence of tumors in a tissue, mechanisms of “nongenotoxic” or toxicity-related carcinogenesis, and xenobiotic activation of carcinogens.
Review and Evaluation of the NCI/NTP Carcinogenesis Bioassays
Authors: Hottendorf Girard H. , Pachter Irwin J.
Published: September 2009

A comparison of the carcinogenesis bioassay results obtained by the National Cancer Institute (NCI) and the National Toxicology Program (NTP) indicates that approximately one-half of the bioassays directed by both institutions were positive for carcinogenicity. The more recent 85 bioassays completed by NTP reveal a higher proportion of studies interpreted as demonstrating no evidence of carcinogenicity than represented in the initial 198 bioassays conducted by NCI. Of the 100 NCI bioassays that were not positive for carcinogenicity 3 (3%) were classified in the category of “no evidence for carcinogenicity in two animal species.” Of the 43 NTP bioassays that were not positive for carcinogenicity 36 (84%) were placed in the category of “no carcinogenic effects.” The reason for this shift from a 33:1 positive to negative ratio in the NCI bioassays to an approximately 1:1 ratio in the NTP bioassays appears to be a difference in interpretation of the adequacy of the testing. For example, 6 of the 36 NTP negative bioassays involved testing in only one species. Uniform criteria for concluding that a bioassay is negative must be developed and the results of all existing and future carcinogenesis bioassays must be interpreted with these exclusive criteria. Other bioassay problems are explored, including the incomplete validation of the carcinogenesis bioassay protocol by confirmatory results with positive and negative reference agents, the apparent lack of bioavailability data for some orally administered negative compounds, the continued use of mouse hepatic neoplasia as a single discriminating parameter, the variability in the inter- and intrastudy incidence of spontaneous tumors, and the continued reliance on the maximum tolerated dose.
Nail Loss and Footpad Erosions in Beagle Dogs Given BW 134U, a Nucleoside Analog
Authors: Szczech George M. , Tucker Walter E.
Published: September 2009

The oral administration of BW 134U to Beagle dogs in a 1-month study was associated with lameness, footpad erosions, and nail loss. Groups of dogs received 60, 120, and 240 mg/kg/day. Compound-related effects were observed in the high dose group and only during the postdose period. Light microscopy revealed prominent cell maturation or radiomimetic defects in the stratum germinativum of the distal phalanges and footpads. The mechanism by which BW 134U produced these cell maturation defects is unknown. There were no signs of adverse effects in other keratin-producing or keratin-containing tissues.
Carcinogenicity Testing of Antitumor Agents
Authors: Hottendorf Girard H.
Published: September 2009

Carcinogenicity testing of antitumor agents in animal bioassays has been proposed because of the potential for carcinogenicity of this class of agents and the expectation that such testing may indicate prospectively the target organs of any related human oncogenesis. The literature reveals the anticipated confirmations in animals of the carcinogenicity of many antitumor agents. Furthermore, these agents have been associated with human tumors in numerous case reports. Review of the literature also indicates the inability of animal studies to predict the sites of carcinogen-induced tumors in man. The carcinogenic risk assessment of antitumor agents should begin with the determination of the ability of the agent to interact with DNA. Those agents which are capable of alkylating or binding DNA should be tested for mutagenic and teratogenic potential. The presumption of carcinogenicity should be made for DNA-reactive, mutagenic/teratogenic antitumor agents without requiring confirmation in long-term carcinogenicity bioassays in large numbers of animals. The inability of carcinogenicity studies in animals to accurately predict potential human tumor sites must also be recognized.
Oesophagostomiasis in Feral Monkeys (Macaca mulatta)
Authors: Lumb George D. , Beamer Parker R. , Rust John H.
Published: September 2009

For periods of 3,6, and 12 months, 104 feral rhesus monkeys (Macaca mulatta) were on test. At the time of necropsy, 26 had caseous granulomatous lesions in the submucosa of the colon consistent with oesophagostomiasis. Five also had histologically identified granulomatous lesions without caseation of various colonic and more distant arterioles. The lesions were seen in the submucosa and subserosa of the colon, the kidney, the adventitial tissue of the prostate, the pancreas, and the heart. Presumptive evidence of the migration of the parasite was found in the adventitial tissue of the esophagus. Fragments of the larvae in arterioles and the caseous submucosa of the colon were consistent morphologically with the species Oesophagostomum. Acellular masses of what was interpreted as cuticle of a molting parasite were found in the lung. A mature female nematode was found encysted in the lung. The identity of that parasite and the cuticle has not been established.
Spermatocytic Seminoma in the Rat
Authors: Kim Sang-Nam , Fitzgerald James E. , De LaIglesia Felix A.
Published: September 2009

During the necropsy of a 2-yr-old untreated control rat from a carcinogenicity study, a tan brown nodular mass was observed within the tunica albuginea of one testis. Both testes were processed for light and transmission electron microscopy. Histologically, the testicular mass was composed of round to polyhedral cells with distinct cell boundaries, amphophilic cytoplasm, fine nuclear chromatin, and a delicate fibrovascular supporting stroma. Ultrastructurally, the tumor cells displayed features associated with spermatocytic differentiation. Based on the light microscopic and the ultrastructural features, the tumor was considered a spermatocytic seminoma of the testis, a rare tumor in the rat.
Interstitial Cell Tumors in a Young Adult New Zealand White Rabbit
Authors: Zwicker Gary M. , Killinger Joanne M.
Published: September 2009

One case of interstitial cell tumors in the testicles of a New Zealand White rabbit was reported. The rabbit was 8–10 months old and had bilateral testicular lesions. There was no enlargement of either testicle and the lesions were first seen on the cut surface. Light and electron microscopy revealed that the cellular morphology resembled the features observed for this tumor in rats, dogs, and a few other domestic animals in which reports are available.
Cis-Diamminedichloroplatinum (II)-induced Acute Renal Failure in the Rat: Enzyme Histochemical Studies
Authors: Jones Thomas W. , Chopra Shreekant , Kaufman James S. , Flamenbaum Walter , Trump Benjamin F.
Published: September 2009

Enzyme histochemical techniques were utilized to examine the progression and extent of proximal tubular injury during the development of cis-diamminedichloroplatinum (II) (CDDP)-induced acute renal failure. Acute renal failure was induced in male rats by the intraperitoneal administration of 10 mg CDDP/kg body weight. At 6, 24, 48, 72, and 96 hr following treatment, renal function was assessed and tissue was collected for renal morphologic and enzyme histochemical studies. The enzymes examined were γ-glutamyl transpeptidase, alkaline phosphatase, sodium-potassium ATPase (nitrophenyl phosphatase), acid phosphatase, glucose-6-phosphatase, succinic dehydrogenase, α-glycerophosphate dehydrogenase, and lactic dehydrogenase. By 24 hr, the activity of acid phosphatase was reduced throughout the proximal tubule, with the greatest decrease occurring in the P3segment of the proximal tubule located in the outer stripe of the outer medulla. Changes in the histochemical staining of the remaining enzymes were not consistently observed until 48 or, in some cases, 72 hr. These alterations involved all portions of the proximal tubule with the most severe changes involving P3. The results of the enzyme histochemical studies along with the morphologic findings indicating that the initiation of CDDP-induced acute renal failure, first apparent at 48 hr in this model, is associated with cell injury throughout the proximal tubule. The majority of the histochemical changes did not become apparent until late in the course of tubular injury. This suggests that most of the changes in enzyme activity represent nonspecific effects of CDDP-induced tubular injury, as opposed to direct enzyme inhibition by the drug.
Fibrogenic Potential of Intratracheally Instilled Quartz, Ferric Oxide, Fibrous Glass, and Hydrated Alumina in Hamsters
Authors: Renne Roger A. , Eldridge Sandra R. , Lewis Trent R. , Stevens Donald L.
Published: September 2009

As a first step in the development of an animal model for determining the role of pulmonary fibrosis in the etiology and pathogenesis of lung cancer, the fibrogenic potential of quartz, quartz and ferric oxide administered together, fibrous glass, and hydrated alumina were studied by multiple intratracheal instillation in groups of male Lak:LVG Syrian golden hamsters. Dose-related decreases in survival were evident for the groups instilled with the two highest doses of quartz or quartz and ferric oxide. Instillation of quartz or quartz and ferric oxide induced the greatest pulmonary fibrosis in response to the materials tested. However, the dense fibrous tissue present in the lungs in classical human silicosis and in experimental silicosis of rats was not observed in this study. The results of this study indicate that the Syrian golden hamster is not a suitable species for studying the role of quartz-induced pulmonary fibrosis in pulmonary carcinogenesis.
The Pathologic Response of the Liver and Thyroid of the Rat to Potassium Prorenoate (SC-23992)
Authors: Lumb George D. , Rust John H.
Published: September 2009

A 3-month dose range finding study in preparation for a 2-yr carcinogenicity study of potassium prorenoate (SC-23992), a steroid with an antihypertensive profile, is reported. The drug was administered by gavage once daily at doses of 10, 30, and 100 mg/kg/day to Charles River CD rats. Treatment was terminated at 13 weeks and 10 randomly selected animals from each treatment group were killed and necropsied. The remaining 10 animals in each dose group, including controls, were maintained for an additional 4 weeks, in order to investigate reversibility of changes, and then were killed and necropsied. Dose-related increases in thyroid-stimulating hormone (TSH) levels were observed in treated animals of both sexes during the dosing period and the changes were statistically significant and correlated with an increased thyroid weight in females at 13 weeks. Dose-related morphologic changes in the thyroid, observed by light and electron microscopy, were compatible with the effects of TSH stimulation. Liver weights, which increased, were dose-related. In females the increase was statistically significant at the high dose at 2, 4, and 13 weeks. In males it was significant at the high dose at 13 weeks. Microsomal enzyme levels were increased in a time- and dose-related manner with higher values in females than in males. The pattern of enzyme induction was of the type exemplified by pregnenolone-16-α-carbonitrile. Morphologic changes in the liver showed centrilobular hepatocyte enlargement with smooth endoplasmic reticulum membrane proliferation confirmed by electron microscopy. All positive findings returned to normal after the 4-week treatment-free period. The relationship between the thyroid stimulation to liver enzyme induction is of interest. Evidence is presented here that in the presence of SC-23992, TSH stimulation and liver enzyme induction occurred. The possibility that the liver metabolism stimulates the thyroid T3, T4elimination with secondary TSH activity is a possible explanation, but on the basis of existing information, direct action by SC-23992 on the thyroid cannot be excluded.
Morphologic and Cytochemical Properties of Mouse Liver Neoplasms Induced by Diethylnitrosamine and Promoted by 4,4'-Dichlorodiphenyltrichloroethane, Chlordane, or Heptachlor
Authors: Numoto Satoshi , Tanaka Takuji , Williams Gary M.
Published: September 2009

The relationships between the gross appearance, histologic types, and cytochemical characteristics of hepatocellular neoplasms were studied in B6C3F1 mice given the liver carcinogen diethylnitrosamine either alone or followed by the organochlorine pesticides, 4,4'-dichlorodiphenyltrichloroethane, chlordane, or heptachlor as promoting agents. Hepatocellular neoplasms were categorized according to their cytoplasmic staining properties with hematoxylin and eosin. Acidophilic neoplasms more of ten displayed increased activity of alkaline phosphatase than did basophilic neoplasms. The activities of glucose-6-phosphatase and adenosine triphosphatase were decreased in both acidophilic and basophilic neoplasms. There was no difference in the activities of these enzymes or γ-glutamyltranspeptidase between adenomas and carcinomas, although most neoplasms did not display γ-glutamyltranspeptidase. Chlordane or heptachlor exposure increased the alkaline phosphatase activity in neoplastic cells, but not that of other enzymes. The majority of neoplasms displayed a deficiency of iron accumulation. The macroscopic appearance of neoplasms was closely related to their cytoplasmic staining properties and cytochemical characteristics.
Generalized Phospholipidosis Induced by an Amphiphilic Cationic Psychotropic Drug
Authors: Robison Rodney L. , Visscher George E. , Roberts Stanley A. , Engstrom Robert G. , Hartman Howard A. , Ballard Frances H.
Published: September 2009

Numerous amphiphilic cationic drugs cause generalized phospholipidosis in animals; one of these drugs is the Sandoz compound 200–125, a psychotropic agent. During a 6-month toxicity study in Charles River CD rats, a dramatic increase in foamy macrophages was seen in the lungs. A follow-up experiment was done to study the pathologic basis of these changes including a reversibility phase. Generalized phospholipidosis was induced after 4 weeks of 500 mg/kg/day of 200–125 by gavage. Characteristic pulmonary lesions consisted of extensive accumulations of large pale foamy macrophages as well as granular eosinophilic extracellular material. Lipid analyses of lungs showed marked increases in phospholipids (144%) and cholesterol esters (110%) in rats treated with 200–125. Drug metabolism studies employing 14C-labeled 200–125 showed an affinity for the drug to concentrate in the lungs and lymphoreticular system (spleen, lymph nodes) as well as in the adrenals, liver, and kidney. Reversibility of the phospholipidosis was nearly complete 4 weeks after drug withdrawal. The tissue changes were characterized by transmission and scanning electron microscopy. The potential pulmonary toxicity in humans with the amphiphiles is discussed.
Variations in the Histologic Distribution of Rat Bone Marrow Cells with Respect to Age and Anatomic Site
Authors: Cline J. Mark , Maronpot Robert R.
Published: September 2009

Bone marrow cellularity in untreated Fischer 344/N rats was subjectively evaluated in hematoxylin and eosin (H & E)-stained histologic sections from femur, tibia, humerus, sternum, lumbar vertebrae, ribs, pelvis, and skull of 2-, 4-, 7-, 16-, and 24-month-old males. Marrow cellularity varied with age of the rat and bone site sampled. Hematopoietic cellularity was consistently higher in rats less than 4 months of age and less consistently higher in 24-month-old rats versus intermediate age groups examined. The 24-month-old rats had the greatest animal-to-animal variation in cellularity. Site differences in bone marrow cellularity were present and similar at 4, 7, and 16 months. Mean percentage of marrow space occupied by hematopoietic cells ranged from 33–75%. Categories for histologic grading of bone marrow cellularity are presented. Sternum, femur, and humerus are recommended sites for histologic evaluation of bone marrow cellularity from conventional H & E-stained sections. Definitive evaluation and assessment of hematopoietic perturbations should not be solely based on subjective evaluation of routine histologic sections.
Renal Function and Laboratory Evaluation
Authors: Bovee Kenneth C.
Published: September 2009

This paper reviews the normal renal function in relation to common functional tests helpful to detect nephrotoxicity. The measurement of renal blood flow, intrarenal distribution of blood flow, and glomerular filtration rate remain the basic parameters of nephrotoxicity. Renal tubular function is accurately measured by standard clearance tests for solutes including electrolytes, glucose and amino acids. The renal concentrating capacity serves as a sensitive but non-specific measure of renal integrity. The measurement of plasma concentration of some solutes is helpful to identify nephrotoxicity, but is most effective when a profile of solutes is measured over a time period. Urinary protein excretion and particularly the excretion of enzymes may localize the nephrotoxicity in certain tubular segments. Due to the multiple functions of the kidney, no single test or group of tests can be relied upon to detect nephrotoxicity. A battery of tests including screening tests and specific tests to measure glomerular or tubular function must be selected to match the pattern of nephrotoxicity.
Aminoglycoside Nephrotoxicity
Authors: Hottendorf Girard H. , Williams Patricia D.
Published: September 2009

Aminoglycosides are life-saving antibiotics in patients with gram negative sepsis. Renal dysfunction occurs in approximately 10% of all clinical courses of aminoglycosides. Because of close pharmacokinetic and toxicologic similarities, rats are excellent human surrogates for comparing the nephrotoxic potentials of these antibiotics. Comparisons in rats are also more sensitive than clinical comparisons due to the insensitivities of clinical renal function tests, the confounding influences present in seriously-ill patients and the inability to make morphologic comparisons in the clinic. The pathogenesis of aminoglycoside nephrotoxicity is still evolving despite extensive world-wide investigations. However, these investigations have facilitated the identification of several inhibitors of aminoglycoside nephrotoxicity. The clinical usefulness of these inhibitors must still be established.
Cyclosporine Nephrotoxicity
Authors: Ryffel Bernhard , Mihatsch Michael J.
Published: September 2009

Cyclosporine (CSA) is a new immunosuppressant which has selectivity for the immune system and is without systemic side effects at therapeutic doses. In contrast to the cytotoxic class of immunosuppressants, no myelotoxic, teratogenic, mutagenic, or carcinogenic effects were observed. Nevertheless, overdosage may lead to renal dysfunction, which occurs mainly in rats, and of ten complicates its clinical use. The experimental data also showed that significant nephrotoxicity was only caused under specific conditions at therapeutic doses. These conditions included ischemia, heminephrectomy, concomitant administration of nephrotoxic drugs, and/or genetic predisposition. Thus, concomitant renal damage is a prerequisite in order to obtain overt nephrotoxicity at therapeutic CSA doses. Since these conditions cannot be avoided in patients, nephrotoxicity of ten occurs at therapeutic doses in man (45). The rat might be a suitable experimental model of CSA nephropathy displaying similar morphologic and functional changes as observed in man. This model also allows further investigations on the pathogenic mechanisms which are elusive at the present time.
Renal Toxicity of Non-Steroidal Anti-Inflammatory Drugs
Authors: Black Hugh E.
Published: September 2009

Non-steroidal anti-inflammatory drugs represent the most heavily prescribed and used class of drugs in human medicine. Most are derivatives of either salicylates, propionic acid, indoleacetic acid, anthranilic acid, pyrazolone, or oxicams. They depress the synthesis of prostaglandins from arachidonic acid by reversible inhibition of the enzyme cyclooxygenase. In the kidney, prostaglandins PGE2and PGI2modulate the vasoconstrictor effects of angiotensin II, norepinephrine, and vasopressin. In the presence of volume contraction, anesthesia, or disease states associated with high levels of these hormones, prostaglandins regulate glomerular filtration, vascular resistance, and renin secretion. They additionally influence urine volume and sodium content. In man, a syndrome of analgesic abuse that has been identified worldwide occurs more frequently in females than males and can result in severe renal damage, most notably renal papillary necrosis. Most common laboratory animals are relatively resistant to developing the renal lesion associated with NSAIDs unless high doses are given over long periods of time and some withholding of water is introduced into the protocol. Diuresis with 5% dextrose and water is protective. Studies of paracematol and salicylate have demonstrated that these compounds concentrate in the papillary tip of the kidney at concentrations of 4 to 13 times the plasma levels in dogs and rabbits, respectively. Renal papillary necrosis has been described in horses on maintenance doses of phenylbutazone where dehydration or reduced water consumption has occurred. The lesion can be reproduced experimentally if water is withheld during a portion of the dosing interval. An increased incidence of uroepithelial tumors have been reported in patients with a history of analgesic abuse. Mixtures containing phenacetin appear to have been at fault. However, carcinogenicity studies with phenacetin have yielded inconsistent results in laboratory animals.
A Review of Unique Male Rat Hydrocarbon Nephropathy
Authors: Alden Carl L.
Published: September 2009

There is a diverse group of hydrocarbons that induce a specific spectrum of nephropathic alterations. Examples include decalin, an alicyclic hydrocarbon; JP5 jet fuel, a mixture of C12–13 straight and branched chain hydrocarbons; C10–11 isoparaffinic hydrocarbons; Stoddard solvent, a mixture of straight and branched-chain paraffins, naphthenes, and alkyl aromatic hydrocarbons; 2,2,4-trimethylpentane, a branched chain hydrocarbon and d-limonene, an aromatic hydrocarbon. Only male rats develop kidney alterations upon exposure to these chemicals. Other mammals such as female rats, mice, guinea pigs, dogs, and monkeys evidently are refractory to kidney injury upon exposure. The primary effect of decalin is to specifically exacerbate the accumulation of alpha2μ-globulin, a unique protein occurring spontaneously in proximal convoluted tubular epithelial cells only in the mature male rat. Thus, the male rat hydrocarbon nephropathy should not be predictive of a normal human renal response.
Experimental Models for the Sequential Analysis of Chemically-Induced Renal Carcinogenesis
Authors: Hard Gordon C.
Published: September 2009

In order to discriminate non-specific toxicity from the early precursor lesions of neoplasia, emphasis in these studies has been on the use of models requiring only a single administration of chemical. Our interests have focussed on three neoplastic entities in the kidney, renal mesenchymal neoplasia, renal cell carcinoma, and nephroblastoma. Dimethylnitrosamine administered as a single intraperitoneal injection to immature female Wistar rats, pre-conditioned for several days with a no-protein/sugar-only diet, has been used for investigating the complex morphological nature of renal mesenchymal tumors, their pathogenesis and the development of cell culture correlates. The near 100% tumor incidence and its facility for cell culture manipulation makes this a particularly potent model for studying chemical carcinogenesis and the evolution of cell transformation. Discovery that the rat kidney response to DMN was biphasic with respect to the time of treatment led to the subsequent development of a high incidence system for inducing renal adenocarcinoma, using older rats. Renal cell carcinomas could also be induced in mice by a single intravenous injection of streptozotocin. The tumor frequency in female CBA/H/T6J mice was almost 100%, providing a new model for the investigation of renal carcinogenesis in this species. Nephroblastoma has been a poorly comprehended neoplasm in both lower animals and man because of the lack of a high incidence model in conventional laboratory mammals. Recently, we have exploited an increased spontaneous predisposition of the Nb rat to nephroblastoma using a single intraperitoneal dose of N-ethylnitrosourea in pregnant females on day 18 of gestation, producing a frequency of 50% for this tumor type. More potent however, was a system which utilized the partially inbred III VO/J strain of rabbit using the same carcinogen and transplacental route of administration. The resultant incidence of nephroblastomas in the progeny was in excess of 90%, and like their counterparts in man, the neoplasms developed rapidly and had a potential for distant metastasis. Each one of these animal models is suitable for the sequential tracing of tumor pathogenesis, and in depth analysis of the biochemical and molecular mechanisms involved in the initiation and formation of different types of renal cancer.
Spontaneous Lipomatous Tumors in the Kidney of the Crl:CD(SD)BR Rat
Authors: Gordon Lea R.
Published: September 2009

Primary tumors of the rat kidney are uncommon (0.05%) and are most of ten seen in older rats. Nephroblastoma is the most commonly diagnosed tumor, but benign and malignant tumors of epithelial cell and mesenchymal cell origin occur. Lipomatous tumors are occasionally seen, especially in aged rats, and are controversial lesions. They have been variously classified in the literature in lipomas, liposarcomas, and lipomatous hamartomas. In my experience, the range of diagnoses has also included post-inflammatory change and lipidosis. The lipomatous tumors are the focus of discussion for the purpose of defining criteria for the various diagnostic categories. The implications of these diagnostic categories for safety assessment are also discussed.
Experimentally Induced Malignant Hypertension in Beagle Dogs
Authors: Cimprich Ronnie E. , Ziemba Linda J. , Kutz Stephen A. , Robertson John L. , Cockrell Beverly
Published: September 2009

The pathology of malignant hypertension in dogs induced either purposely or inadvertently by the Goldblatt procedure has not been previously reported. Malignant hypertension was experimentally produced in beagle dogs by a modified Goldblatt procedure; in a single surgical procedure, one kidney was removed and the blood flow to the remaining kidney was reduced by 50%. A sudden onset of severe clinical signs developed within one to three weeks after surgery. The dogs were markedly depressed or in shock, were vomiting, and had either bloody feces or bloody diarrhea. Hematologic changes compatible with a diagnosis of microangiopathic hemolytic anemia consisted of hemolysis, thrombocytopenia, and the presence of burr cells and schistocytes. Some dogs had neutrophilia and slight to moderate increases in blood urea nitrogen and creatinine. At necropsy, there were gross hemorrhages in the heart, brain, urinary bladder, and gastrointestinal tract. Histologic findings consisted of multifocal parenchymal hemorrhage, fibrinoid necrosis of arterioles, medial smooth muscle hyperplasia, adventitial fibroplasia and mononuclear cell infiltrates, and microthrombi. The vascular clamp most likely protected the kidney from the systemic hypertension since the remaining kidney was largely not remarkable by light or electron microscopy. The dog appears to be a good model to study the pathology of malignant hypertension and microangiopathic hemolytic anemia.
Histopathology and Cell Proliferation Induced by 2,2,4-Trimethylpentane in the Male Rat Kidney
Authors: Short Brian G. , Burnett Vicki L. , Swenberg James A.
Published: September 2009

Unleaded gasoline causes acute and chronic nephrotoxicity and renal tumors in male rats, but not female rats or mice of either sex. An active nephrotoxic component of unleaded gasoline has been identified as 2,2,4-trimethylpentane (TMP). The first objective of this study was to characterize light microscopic renal lesions induced in male F344 rats by a 21-day gavage regimen of 50 to 500 mg/kg TMP. The second objective was to localize and quantitate sites of renal cell proliferation induced by the same TMP dose regimens using histoautoradiographic analysis after [3H]thymidine incorporation. Light microscopic lesions in the proximal convoluted tubule consisted of protein droplet and crystalloid body accumulation, degeneration, and necrosis, and were similar to lesions noted in previous inhalation and gavage studies with other hydrocarbon compounds. The above renal lesions were not dose-related, although tubular dilation of thin limb segments with granular cell debris was dose-related. In cell proliferation studies TMP induced a non-dose-related five- to sixfold increase in the labelling index of the same proximal convoluted tubule portions (P2 segment) that contained severe crystalloid body accumulation, degeneration, and necrosis. Less pronounced, but statistically significant (p ≤ 0.05), increases in cell proliferation were also observed in other nephron segments, indicating a generalized regenerative response of the kidney to TMP. The cytotoxic and regenerative renal effects of TMP administered by gavage suggest that similar mechanisms may be involved in the induction of kidney tumors in male rats following chronic inhalation exposure to unleaded gasoline.
Effects of Cyclosporine on Human Endothelial Cell Cultures
Authors: Trifillis Anna L. , Hall-Craggs Mary
Published: September 2009

Reports of vascular changes in renal biopsies of transplant patients treated with cyclosporine prompted review of our own renal biopsies and examination of human endothelial cell cultures exposed to cyclosporine in vitro Endothelial cells were isolated from human umbilical cords by collagenase digestion and cultured in Medium 199 with Earle's salts plus 20% pooled human serum in the absence of antibiotics. Cultures exposed to cyclosporine (0, 0.4, 1.0, 5.0, 10.0 μg/ml) for 0, 3, 7, 10, and 14 days were subsequently fixed in 2% glutaraldehyde in 0.1m cacodylate buffer. Vascular thrombosis was seen in renal biopsies of cyclosporine-and azathioprine-treated patients but the incidence was the same in both groups. No change in the morphology of endothelial cell cultures was observed until 7 days when an increase in size and number of cytoplasmic inclusions became apparent in both control and cyclosporine-treated cultures. By electron microscopy, these inclusions were identified as secondary lysosomes. Their number and size increased with the length of time in culture but did not appear to correlate with the concentration of cyclosporine in the medium. No other morphologic change was identified. It is concluded that the appearance of increased numbers of secondary lysosomes in human endothelial cell cultures is a function of culture age as opposed to cyclosporine exposure. Furthermore, the data indicate that small vessel thrombosis is not specific to treatment with cyclosporine.
Sequential Morphologic Analysis of the Nephrotoxicity Produced in Rats by Single Doses of Chlorozotocin
Authors: Dees Jane H. , Kramer Robert A.
Published: September 2009

Chlorozotocin is a chloroethylnitrosourea antitumor agent that is in clinical trial for a variety of human tumors. Renal failure has been a reported side effect of treatment with several of the chloroethylnitrosoureas, including chlorozotocin. To better understand the pathogenesis of this target organ toxicity, we have studied the nephrotoxicity of a single high, intermediate, or low dose of chlorozotocin in male F344 rats. We report here the sequence of histopathologic changes seen over a 1–10-day (high dose) or 1–28-day (intermediate or low dose) period. The single high dose (40 mg/kg, s.c.) produced an acute cortical necrosis involving the proximal tubules, followed by later necrotic changes in the collecting ducts in the inner medulla. Karyomegaly was noted at 10 days in occasional cells of the papillary collecting ducts and urinary epithelium lining the papilla. A single intermediate dose (25 mg/kg, s.c.) caused a similar but less severe injury of later onset. Proximal tubule injury was less severe and more limited. Necrosis of papillary collecting ducts was not seen; however, karyomegaly was pronounced in cells of the collecting ducts in the inner stripe of the outer medulla and inner medulla, and in the urinary epithelium covering the papilla. No discernible histopathology was present following the low dose (12.5 mg/kg, s.c.) of chlorozotocin. The histopathology was correlated with biochemical parameters. Our findings have possible implications for monitoring the severity of nephrotoxic side effects in patients, as well as provide preliminary evidence that this antineoplastic agent may itself cause preneoplastic changes, a finding with important long term implications.
The Effect of Gentamicin on Human Renal Proximal Tubular Cells
Authors: Regec Annette L. , Trifillis Anna L. , Trump Benjamin F.
Published: September 2009

Human renal proximal tubular cells were exposed to gentamicin (0,0.1,0.5,1.0, 5.0,10.0 mg/ml medium) for 3,7,10, and 14 days. Cells were counted and cell viability was estimated by lactate dehydrogenase release. In addition, brush border-associated ( γ-glutamyltransferase) and lysosomal (acid phosphatase, N-acetyl- β-glucosaminidase, and sphingomyelinase) enzyme activities were measured (0.01, 1.0, 3.3 mg/ml gentamicin for 3, 7, 10 and 14 days). The number of cells did not change significantly after gentamicin treatment. Cell viability, however, significantly decreased after 3 and 7 days exposure to 5 and 10 mg/ml gentamicin. Total lactate dehydrogenase activity was significantly decreased at 7, 10, and 14 days exposure to gentamicin ≥5.0 mg/ml. γ-Glutamyltransferase, acid phosphatase, and sphingomyelinase were decreased at 3, 7, and 10 days exposure to gentamicin ≥ 1.0 mg/ml. Continued exposure to gentamicin ≤ 1.0 mg/ml appeared to have little or no effect on the activity of these enzymes at 14 days. N-Acetyl- β-glucosaminidase activity, in contrast, was elevated (120–140% control) in the gentamicin-treated (≥ 1.0 mg/ml) groups at all time periods studied. Thus, gentamicin exposure resulted in changes in some of the enzyme activities in human renal proximal tubular cell cultures, but longer exposure (14 days) to gentamicin (≤ 1.0 mg/ml) resulted in a return to control levels of some activities.
Strain-related Susceptibility to Nephrotoxicity Induced by Aspirin and Phenylbutazone in Rats
Authors: Owen Roger A. , Heywood Ralph
Published: September 2009

Single doses of aspirin induce scattered foci of necrosis of proximal tubules in some strains of rats, whereas acute or sub-acute administration of phenylbutazone causes renal papillary necrosis. Initially, using Sprague-Dawley rats of CFY and CD strains, it became clear that these rats were not as susceptible to these drugs as the literature suggested. Aspirin-induced necrosis was apparently sex-related, being seen in females but could be induced by hormone treatment in males. Male Wistar and Sprague-Dawley rats had reacted differently to administration of phenylbutazone for two weeks. Two experiments were performed with four rat strains: Wistar, Lister-Hooded, Sprague-Dawley, and Fischer-344. The rats were six weeks old at the start of the experiments. Five males and five females of each strain were gavaged with either a single dose of 1,000 mg/kg of aspirin or 200 mg/kg phenylbutazone once daily for four weeks. The drugs were suspended in methylcellulose, which was given to equal numbers of control male and female rats in each experiment. The rats were maintained under standard conditions. Blood and 18-hour overnight urine samples were collected prior to sacrifice. There were no strain-related differences in the types of renal lesions seen, however there were differences in the degrees of responses to the two drugs. With aspirin the female Fischer-344 rats were the most susceptible showing necrosis of proximal tubules of both kidneys and markedly elevated urinary protein concentration and gamma-GT activity. Other females showed less change. Male rats were affected only slightly and males of the Wistar strain were not. Thus, the greater susceptibility of female rats to aspirin-induced nephrotoxicity was confirmed. Phenylbutazone killed two female and one male Wistar rats with gastrointestinal ulceration after three doses. Fischer-344 rats also showed reaction to the drug. For these two strains the dosage was reduced to 50 mg/kg/day for the remainder of the study. At the end of the dosing period one or more rats from each strain showed renal papillary necrosis. Thus, strain differences occurred in the susceptibility of the rats to phenylbutazone but this was not seen in the nephrotoxicity profiles.
Histopathological Study of Human Cisplatin Nephropathy
Authors: Tanaka Hisako , Ishikawa Eisei , Teshima Shinichi , Shimizu Eiji
Published: September 2009

The present study was conducted to obtain detailed information on the morphological changes in the human kidney as related to cisplatin therapy. The kidneys of ten autopsy cases showing impaired renal function following cisplatin therapy with hydration were examined histologically. Sporadic lesions of degeneration, necrosis, and regenerative changes were observed in the pars convoluta and pars recta of the proximal tubule, distal tubule, and collecting duct. Enlarged and pleomorphic nuclei in regenerated epithelial cells and hyperplasia of the collecting duct lining cells were considered to be specific histological findings in renal injury related to cisplatin therapy. Electron microscopic examination of a case receiving a large dose of cisplatin without signs of renal insufficiency showed an increased number of cytosomes containing electron dense granules in all tubular portions and conspicuous nuclear indentation in the thin limb of the loop of Henle and collecting duct. The platinum concentration in autopsy organs and biopsy cases was analyzed, but no correlation could be found between the concentration level of platinum in the kidney and impairment of renal function.