Cancer In Sprague-Dawley Rats Research Articles

Chemically Induced Brain Cancer in Sprague-Dawley Rats: Changed Lipidomics Mimics the Human Conditions

Malignant gliomas are one of the most treatment-refractory cancers. Development of resistance to chemo- and radiotherapies contributes to these tumors’ aggressive phenotypes. Elevated lipid levels in gliomas have been reported for the last 50 years. However, the molecular mechanisms of how tumor tissues obtain lipids and utilize them are not well understood.In our study, 48.6% of phosphatidylcholines were significantly changed during an early stage of brain cancer in females, and 66.2% in males. As for lysophosphatidylcholines 57.1% metabolites were significantly changed in female, and 64.3% in male rats. We observed the most interesting results in the group of sphingomyelins, where 85.8% metabolites were significantly elevated during brain cancer. According to VIP projection, the most important metabolites were: PC ae C40:3, PC ae C38:1, PC ae C30:1, PC ae C38:3, PC ae C44:3, PC aa C40:2, PC aa C42:0, PC ae C30:2, SM C20:2, PC aa C42:1 in females, and PC ae C38:1, PC ae C40:3, PC ae C30:1, PC ae C42:1, SM C20:2, PC aa C34:4, PC ae C38:4, PC aa C32:2, PC aa C38:5, lysoPC a C14:0. The identification of lipid biomarkers during the early stage of cancer could improve patient prognosis.

Zingiberene exerts chemopreventive activity against 7,12-dimethylbenz(a)anthracene-induced breast cancer in Sprague-Dawley rats.

Breast cancer is the primary cause of cancer-related death in females, wherein increased mortality of breast cancer patients is recorded worldwide. Zingiberene is a monocyclic sesquiterpene from the ginger plant and has many pharmacological benefits. In this exploration, we assessed the anticancer actions of Zingiberene against the 7,12-dimethylbenz(a)anthracene (DMBA)-stimulated mammary carcinogenesis in rats and MDA-MB-231 cells. Breast cancer was induced in the Female Sprague-Dawley rats through the 25 mg/kg of DMBA in 0.5 ml of corn oil and then treated with 20 and 40 mg/kg of Zingiberene, respectively. The body weight of animals and tumor volume was measured. Hematological parameters, transaminases, lipid profile, lipid peroxidation, and antioxidants status were scrutinized using standard techniques. The estrogen receptor-α and inflammatory markers were inspected by using respective assay kits. Histological damage scores were determined. In vitro experiments were conducted to scrutinize Zingiberene's effect on cell viability and apoptotic cell death in MDA-MB-231 cells. Zingiberene substantially modulated the DMBA-stimulated physiological and hematological changes and decreased the transaminases, and lipid peroxidation in the DMBA-stimulated animals. Zingiberene also elevated the antioxidant level and suppressed the inflammatory markers. Histological study revealed the protective effects of Zingiberene. The viability of MDA-MB-231 cells was noticeably diminished by the Zingiberene, thus inducing apoptotic cell death. Overall, our findings reliably proved the anticancer potential of Zingiberene against the DMBA-stimulated mammary tumorigenesis, and it could be a promising chemotherapeutic agent.

INHIBITORY ACTIVITY OF SNAIL (Achatina fulica (Lam.) Bowdich) MUCUS ON GROWTH OF MAMMARY CANCER IN RAT INDUCED WITH DMBA (7,12-DIMETHYLBENZ(α)ANTHRACENE)

Back to nature as a medication concept has been accepted widely because it has fewer side effects than modern medicines. Researches on natural products as anticancer agent therapies are in progress. This present research was conducted to determine that the inhibitory activity of snail (Achatina fulica (Lam.) Bowdich) mucus inhibits the growth rate of mammary cancer in SpragueDawley rats. Five groups of female rats, with four individuals each, were induced with 7,12-dimethylbenz(α)anthracene (DMBA) for five weeks. Snail mucus was applied every seven days to the treated rats with three different dosages (15, 20, and 25 mg/kg BW). Observations were done on diameters and growth rate of the mammary cancer lump developed at the end of week 8, 10, 12, 14, and 16. Histopathological examination was carried out at the end of the 16th week. Inhibitory activity results showed a row of average diameter of the cancerous lumps on rats with the following details. The results obtained from the application of snail mucus at dosage of 15, 20, and 25 mg/kg BW were at 0.40, 0.60, and 0.09 cm respectively along with average growth rate of cancerous lumps at 1.50, 0.75, and 0.25. The histopathology results of the snail mucus treatment at dosage of 15, 20, and 25 mg/kg BW showed normal tissue depiction and similarly normal histopathological form indicated by the presence of their sub-clinic components. The results showed that a snail mucus dose of 25 mg/kg BW was able to perform inhibitory activity on growing mammary cancer in rats induced by DMBA.

Defensive Consequences of Hydroalcoholic Extract and Isolated Compounds of Ipomoea aquatica Forsskal against DMBA Method

Introduction: Beyond the preceding twenty years progresses in investigative systems and an upsurge in effect usage routes have remarkably enhanced breast cancer endurance proportions, regardless of a cumulative number of identified cases amongst women. Certain plant extracts have been acquired to produce anti-cancer powers and to fit into chemotherapy treatments. Aim and Objective: To accomplish the anticancer activities of phytoconstituents of Ipomoea aquatica Forsskal beside DMBA induced breast cancer in Sprague dawley rats with the addition of assessment of histopathological and biochemical parameters. Methods: There were six groups of animals such G1 (Normal), G2 (tumor), G3 (standard Vinblastine), G4 (hydroalcoholic extract), G5 (Isolated compound I) and G6 (Isolated compound II) correspondingly. Results and discussion: The body weight, defense percentage and tumor volume were determined. A substantial behaviors were detected in G3 (37.85%), G4 (24%), G5 31.70% and G6 (32.65%) after 45 days therapy. The special effects of antioxidant enzymes similar to SOD, CAT, GPX and LPx were examined and had revealed statistically significant findings. Conclusion: Bearing in mind regarding the prolonged medication of patients, natural resolves (plant of interest with its isolated compounds) will control superior deprived of any side effects to cure the ailment in effectual approach.

Quinazolinone derivative BNUA-3 ameliorated [NDEA+2-AAF]-induced liver carcinogenesis in SD rats by modulating AhR-CYP1B1-Nrf2-Keap1 pathway.

Cytochrome P450 1B1, considered as one of the novel chemotherapeutic targets involved in cancer prevention and therapy is also associated with the conversion of procarcinogens into their active metabolites. The aryl hydrocarbon receptor (AhR) is responsible for mediating different biological responses to a wide variety of environmental pollutants and also causes transcriptional activation of cytochrome P450 enzymes including CYP1B1 and thus plays a pivotal role for initiating cancer and its progression. On the other hand, active carcinogenic metabolites and reactive oxygen species-mediated stress alter different molecular signalling pathways and gene expressions. Quinazoline derivatives are recognized for their diversified biological activities including anticancer properties. The current study was designed for evaluation of chemotherapeutic efficacy of a synthetic quinazolinone derivative BNUA-3 against hepatocellular cancer in Sprague-Dawley (SD) rats. A detailed in vivo analysis was performed by administrating BNUA-3 (15, 30mg/kg b.w. for 28days, i.p.) in N-Nitrosodiethylamine+2-Acetylaminofluorene induced partially hepatectomized liver cancer in SD rats. This was followed by morphological evaluations, biochemical estimations and analysis of different mRNA and protein expressions. The results demonstrated the potency of BNUA-3 in efficient restoration of the altered morphology of liver, its protective effect against lipid peroxidation, enzymic and non-enzymic antioxidants levels in liver tissue which was disrupted after cancer induction. The study also demonstrated downregulation of AhR, CYP1B1 and Keap1 expressions with subsequent augmentation of protective Nrf2, HO-1, NQO1 and GSTA1 expressions thus, revealing the chemotherapeutic potency of BNUA-3 in inhibiting liver carcinogenesis through AhR/CYP1B1/Nrf2/Keap1 pathway.

Herniarin, a natural coumarin, inhibits mammary carcinogenesis by modulating liver X receptor-α/β-PI3K-Akt-Maf1 Pathway in sprague-dawley rats

Background: The massive tumor burden following breast cancer initiation requires a constant supply of energy achieved by modification of different metabolic pathways. Enhanced lipid synthesis associated with glucose metabolism modification triggered by a battery of signaling events promotes unregulated cell division and growth. Coumarins with their diversified bioactivity are also recognized for their therapeutic efficacy in breast cancer. Objectives: Thus, this study was performed to assess the chemotherapeutic potential of herniarin (HER), a 7-methoxycoumarin derivative against polycyclic aromatic hydrocarbon-induced mammary cancer. Materials and Methods: In silico molecular docking was carried out to identify the interactions of HER with LXR α and β, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCoAR), PI3K, and Akt followed by in vitro evaluation of HMGCoAR inhibitory potential of HER. Detailed in vivo studies was then performed in 7,12-dimethylbenz(a) anthracene-induced breast cancer model in Sprague-Dawley (SD) rats using HER at doses 20 mg/kg, b. w. and 40 mg/kg, b. w. along with molecular-level analysis (messenger RNA and proteins) by real-time quantitative polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay. Results: The docking studies revealed a significant binding affinity of HER to the aforesaid receptors and its HMGCoAR inhibitory potential (IC50 =103.1 nM) validated the docking studies. HER successfully re-established the lipid and lipoprotein levels along with the activities of lipid-metabolizing enzymes and glycolytic enzymes that were altered following cancer induction. The molecular biology evaluations reflected the efficiency of HER as it evidently alleviated the overexpression of HMGCOAR, PI3K, and Akt along with the lipogenic genes fatty acid synthase and acetyl-CoA carboxylase 1 in the carcinoma-developed animals by upregulating LXR (α and β) and Maf1. Conclusion: The bioactive moiety HER efficiently controlled alterations in metabolic pathways, thus balancing energy consumption, attenuating tumor progression through LXR/PI3K/Akt/Maf1 axis in breast cancer in SD rats.

Administration of probiotic lactobacillus rhamnosus GG together with celecoxib attenuates oxidative stress and modulates colonic morphology in 1,2-dimethylhydrazine-induced colon cancer in sprague dawley rats

Administration of probiotic lactobacillus rhamnosus GG together with celecoxib attenuates oxidative stress and modulates colonic morphology in 1,2-dimethylhydrazine-induced colon cancer in sprague dawley rats

Abstract 5255: Comparison of high-fructose and standard diets in methylnitrosourea (MNU)-induced ER+ mammary cancers: Altered carcinogenesis, differential effects of metformin, and metabolomic differences

Abstract The MNU-induced model of ER+ mammary cancers in Sprague-Dawley rats has routinely been employed in screening for chemopreventive agents. We recently reported that metformin was ineffective in preventing mammary cancers in rats on a standard diet (Thompson, et al, Cancer Prev. Res, 8, 231-9, 2015). In this study, we evaluated the carcinogenic response in Vehicle-treated rats and rats receiving Metformin (150 mg/Kg BW/day) on standard Teklad or isocaloric High-Fructose diets. In the first study, rats were placed on Teklad or High-Fructose diet at 43 days of age. At 100 days of age, animals were administered a single dose of MNU. Animals were administered Metformin or tamoxifen beginning 5 days later. Rats were palpated weekly for mammary tumors and sacrificed at 300 days of age. Body weights between groups were not different. Tumor multiplicity and tumor weights were: Vehicle-Teklad,1.15 and 1.44g; Vehicle- High-Fructose, 2.10 and 2.94g; Metformin-Teklad, 1.25 and 1.91g; Metformin -High-Fructose, 1.00 and1.99g. Tamoxifen resulted in the prevention of all tumors. High-Fructose alone resulted in a 2X increase in tumor multiplicity (P<0.05) and tumor weights (P<0.05). In the Teklad diet, Metformin marginally increased tumor multiplicity and weights (0.1>P<0.05). In the High-Fructose diet, Metformin decreased tumor multiplicity by 50% (P>0.05). In the second study, which parallels the standard MNU model, rats were also placed on Teklad or High-Fructose diet at 43 days of age. At 50 days of age, rats were administered a single dose of MNU. Rats on High-Fructose diet were administered either Vehicle or Metformin, while rats on Teklad diet were given only Vehicle; beginning 5 days later. Rats were palpated weekly and sacrificed at 170 days of age. Body weights between groups were not different. Tumor multiplicity and tumor weights were: Vehicle-High-Fructose, 6.00 and 7.74g; Metformin High-Fructose, 5.00 and 6.17g; and Vehicle-Teklad, 2.70 and 5.75g. As indicated, Vehicle-treated rats on High-Fructose diet had twice the number of cancers as Vehicle-Teklad diet (P<0.05). Metformin had a minimal effect in rats on a High-Fructose diet; unlike our previous results in rats ( receiving MNU at 50 days of age) on Teklad or High-Fat diet where metformin increased cancer multiplicity and cancer weights. Furthermore, we performed metabolomic studies on both serum and cancers from animals on Teklad and High-Fructose diets. It was observed (based on principal component analysis) that serum from rats on High-Fructose and standard Teklad diet were profoundly different. Furthermore, there appeared to be a metabolic signature in rats bearing cancers. These and other metabolomic changes will be presented. Supported by NCI contract number HHSN261201200021I, Task Order HHSN26100005. Citation Format: Mark S. Miller, Clinton J. Grubbs, Steve Stirdivant, Ronald A. Lubet. Comparison of high-fructose and standard diets in methylnitrosourea (MNU)-induced ER+ mammary cancers: Altered carcinogenesis, differential effects of metformin, and metabolomic differences [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5255. doi:10.1158/1538-7445.AM2017-5255

In-vivo Anti-tumor Evaluation of Dihydroartemisinin-Derived Endodisulphide on MNU-induced Liver Cancer in Sprague-Dawley Rats

In-vivo Anti-tumor Evaluation of Dihydroartemisinin-Derived Endodisulphide on MNU-induced Liver Cancer in Sprague-Dawley Rats

Abstract 837: Reproducibility of efficacy results for chemopreventive agents in the methylnitrosourea-induced rat mammary cancer model

Abstract Perhaps the greatest question in biological science is: Can results be reproduced? This problem is of particular concern for a group whose primary mission is to screen for potentially effective agents and rank results by activity. The reproducibility of testing specific agents for chemopreventive activity, testing the same agent in various protocols, and testing multiple agents of a given mechanistic class in the MNU-induced model of ER+ breast cancer in Sprague-Dawley rats is presented. The model employs female virgin Sprague-Dawley rats on a standard 4% Teklad diet which develop ER+ mammary cancers (adenocarcinomas) following MNU injection at 50 days of age (DOA). Preventive agents were given by gavage or diet starting at 55 DOA, and animals monitored for tumor development until approximately 170 DOA. Seven agents which we had previously studied and which were strongly positive [tamoxifen, vorozole (an aromatase inhibitor), Targretin, gefitinib] or strongly negative (naproxen, Lipitor, metformin) were examined in the assays presented. These study results confirmed our previous data. We next tested these same agents in animals given a Western diet (high fat, low calcium) and again obtained the same results. We had thought that the altered physiology and potentially altered pharmacokinetics of rats on a Western diet might alter the observed chemopreventive efficacy. These studies show that the direct repetition of clearly positive and negative agents can be achieved and, in fact, repeated with a significant variation in diet. Importantly, in terms of reproducibility, we find that multiple agents of the same mechanistic class give similar results. Thus, various SERMs (tamoxifen, toremifene, Arzoxifene), RXR agonists (targretin, UAB-30, 4Me-UAB-30), EGFR inhibitors (gefitinib, Erlotinib, lapatinib) are all highly positive (70-95% reduction of cancer multiplicity). In contrast, the negative classes COX inhibitors (naproxen, sulindac, aspirin) or statins (atorvastatin or simvastatin) have been consistently negative (<20% reduction). Therefore, reproducibility of efficacy results appears to be quite solid in our chemoprevention agent development program for rat mammary cancer testing, and we can, with significant certainty, trust our results. Citation Format: Vernon E. Steele, Ronald A. Lubet, Clinton J. Grubbs. Reproducibility of efficacy results for chemopreventive agents in the methylnitrosourea-induced rat mammary cancer model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 837.

Evaluation of oral bioavailability and anticancer potential of raloxifene solid lipid nanoparticles.

The objective of the present investigation was formulation of raloxifene loaded solid lipid nanoparticles (R-SLN) for oral administration and evaluation of its anticancer potential in 7,12- dimethylbenzanthracene (DMBA)-induced breast cancer in Sprague-Dawley rats. Optimized R-SLN formulation prepared by modified micro-emulsion method resulted in R-SLN of 288.0±28.5 nm size and 95.56% entrapment efficiency. R-SLN exhibited in vitro prolonged release of raloxifene for 72 h in phosphate buffered saline. R-SLN was stable in simulated gastro-intestinal (GIT) fluids consisting of pH 1.2, pH 7.4, simulated gastric fluid and simulated intestinal fluid. A two-fold increase was observed in raloxifene oral bioavailability from R-SLN. R-SLN exhibited enhanced efficacy and chemopreventive activity over pure raloxifene as indicated by evaluation of tumor burden (P < 0.001) and tumor incidence (P < 0.001). The results indicate the potential of raloxifene solid lipid nanoparticles in optimizing chemoprevention of breast cancer by R-SLN.

Free radical scavenging and antioxidant activity of D-pinitol against 7, 12 dimethylbenz (a) anthracene induced breast cancer in sprague dawley rats

ObjectiveTo investigate whether D-pinitol efficiently scavenge free radicals using various in vitro models [1, 1-diphenyl-2-picrylhydrazyl (DPPH), nitric oxide, superoxide anion and total antioxidant activity] and in vivo models. MethodsFemale Sprague-Dawley rats (150-160 g) were divided into four groups and each group consisting of six animals. Group I and group IV were vector and drug control. The group II and group III animals were treated with 7, 12-dimethylbenz(a)anthracene (DMBA) 20 mg/kg body weight to induce mammary carcinoma. Rats received cancer bearing Group III animals were treated with D-pinitol at the concentration of 200 mg/kg bodyweight for 45 d orally. Five different concentrations of D-pinitol (100 to 500 μg/mL) were used in in vitro studies. ResutlsThe results revealed that D-pinitol efficiently scavenges DPPH radicals and the IC50 was found to be 290 μg/mL and it also exhibited a dose dependent antioxidant activity at different concentrations. In addition, the superoxide and nitricoxide radicals were also significantly inhibited by D-pinitol at the concentrations of 360 and 390 μg/mL respectively. On the other hand, D-pinitol has significantly increased antioxidant enzymes during DMBA induced mammary carcinoma. ConclusionsIt can be concluded from the investigation that D-pinitol has an excellent antioxidant activity which could be due to the scavenging capacities on the stable DPPH radicals, superoxide, nitric oxide and DMBA induced free radicals thereby it exhibits remarkable total antioxidant activity.

Evaluation of bioavailability, efficacy, and safety profile of doxorubicin-loaded solid lipid nanoparticles

We investigated the bioavailability, efficacy, and toxicity of doxorubicin-loaded solid lipid nanoparticles (DOX-SLNs) prepared by a simple modified double-emulsification method. A 3-factor, 3-level Box–Behnken statistical design was adopted in the optimization of DOX-SLN formulation considering dependent factors particle size and entrapment efficiency. Optimized SLN formulation composed of lipid (2 %) consisting of soya lecithin and Precirol ATO 5 (1:3) with Pluronic F68 (0.3 %) resulted in 217.36 ± 3.31 nm particle size and 59.45 ± 1.75 % entrapment efficiency. DOX-SLN exhibited significant enhancement (p < 0.05) in bioavailability as compared with free DOX in Sprague–Dawley (SD) rats. DOX-SLN exhibited higher peak plasma concentration (6.761 ± 0.08 vs. 2.412 ± 0.04 μg/ml), increased AUC (61.368 ± 3.54 vs. 5.812 ± 0.49 μg/ml h), decreased clearance (36 ± 0.01 vs. 619 ± 0.005 mL/h kg), and volume of distribution (733 ± 0.092 vs. 2,064 ± 0.061 mL/kg) when compared to free DOX. The collective results of cardiac and kidney enzyme assay, antioxidant enzyme levels, hematological parameters, effect on body weight and tumor volume, tumor necrosis factor-α level, histopathological examination, and survival analysis confirmed the improved efficacy and safety profile of DOX-SLN in 7,12-dimethyl benzanthracene-induced breast cancer in SD rats.

Anticancer activity of fungal taxol derived from Botryodiplodia theobromae Pat., an endophytic fungus, against 7, 12 dimethyl benz(a)anthracene (DMBA)-induced mammary gland carcinogenesis in Sprague dawley rats

Breast cancer is the second most prevalent cancer worldwide and their incidence increases gradually. Taxol (paclitaxel), a potent anticancer drug, is naturally isolated from the bark of the Pacific yew. Taxol is widely used in the treatment of ovarian, lung and breast cancer. The increased demand for taxol, coupled with its limited availability from the protected Pacific yew, has had researchers scrambling for alternate sources. The purpose of the present study is to investigate chemopreventive effect of fungal taxol derived from a novel endophytic fungus Botryodiplodia theobromae Pat., isolated from a medicinal plant Morinda citrifolia Linn. The fungal taxol is found to be active against the 7, 12 dimethyl benz(a)anthracene (DMBA)-induced mammary gland carcinogenesis in Sprague dawley rats. The enzymic and non-enzymic antioxidants i.e. superoxide dismutase (SOD), catalase (CAT), glutatione peroxidase (GPx), glutatione-S-transferase (GST), reduced glutathione (GSH), vitamin C and vitamin E were evaluated in control and experimental groups. Lipid peroxides levels (LPO) were also tested. Histological analysis of breast tissue was analyzed by haematoxylin and eosin staining to assess the cytoprotective role of fungal taxol active against breast cancer. Immunohistochemical analyses were also performed to evaluate the effect of fungal taxol on the inflammatory marker such as Cyclooxygenase-2 (COX-2) in control and experimental groups. The results showed that the fungal taxol significantly suppresses the DMBA-induced breast cancer in Sprague dawley rats.

Effects of 50- or 60-hertz, 100 microT magnetic field exposure in the DMBA mammary cancer model in Sprague-Dawley rats: possible explanations for different results from two laboratories.

In line with the possible relationship between electric power and breast cancer risk and the underlying melatonin hypothesis, 50-Hz magnetic field (MF) exposure at microtesla flux densities for either 13 or 27 weeks significantly increased the development and growth of mammary tumors in a series of experiments from Löscher's group in Germany. Löscher's group used the 7,12-dimethylbenz[a]anthracene (DMBA) model of breast cancer in Sprague-Dawley rats. The finding could not be replicated when a similar experimental protocol was used in a study conducted by Battelle in the United States. In the present paper, investigators from the two groups discuss differences between their studies that might explain the apparent discrepancies between the results. These differences include the use of different substrains of Sprague-Dawley rats (the U.S. rats were more susceptible to DMBA than the European rats), different sources for diet and DMBA, differences in environmental conditions, and differences in MF exposure metrics. Furthermore, the effects of MF exposure reported by Löscher's group, albeit significant, were weak. We also discuss the general problem of replicating such weak effects.

Exposure of Female Rats to a 100-μT 50 Hz Magnetic Field Does Not Induce Consistent Changes in Nocturnal Levels of Melatonin

The hypothesis whereby alternating (50 or 60 Hz) magnetic fields such as those produced by electric power reduce the nocturnal production of melatonin in the pineal gland and thereby indirectly enhance development and growth of breast cancer has attracted a great deal of interest. In view of the potential importance of this hypothesis that there is a link between electric power and breast cancer, which is also known as the "melatonin hypothesis", we undertook various experiments in female Sprague-Dawley rats to evaluate whether 100-microT 50 Hz magnetic-field exposure, i.e. a flux density shown recently to exert a tumor (co)promoting effect in the 7,12-dimethylbenz[a]anthracene (DMBA) model of breast cancer in Sprague-Dawley rats, consistently reduces melatonin levels and, if not, which factors may be involved in the inconsistent effects of magnetic-field exposure on production of melatonin. Long-term exposure of female Sprague-Dawley rats to magnetic fields for 13 weeks did not alter the nocturnal levels of melatonin in the pineal gland or serum (determined 5 h after the onset of darkness) significantly, irrespective of whether rats were treated with DMBA or not. In one experiment, when blood was sampled 3, 5 and 6 h after the onset of darkness after 2 weeks of magnetic-field or sham exposure, a significant decrease in melatonin was seen in magnetic-field-exposed rats at 6 h. However, the results could not be reproduced in two subsequent experiments in other groups of rats. Shorter (1 day, 1 week) or longer (4, 8, 13 weeks) exposure periods also did not result in any significant effects of the magnetic field on melatonin levels when blood sampling was performed either 5 or 6 h after onset of the dark phase. Various potential sources of variation in melatonin levels or in magnetic-field effects on melatonin levels were evaluated, but the reason(s) for the inconsistent effect of magnetic-field exposure remains unclear. Thus the present study failed to demonstrate a consistent effect of 100-microT 50 Hz magnetic-field exposure on melatonin levels in Sprague-Dawley rats.

Long-Term Effects of Combined Exposure to Fission Neutrons and Inhaled Cadmium Chloride in Rats

The results of several epidemiologic studies in the U.S.A. (Thun et al., 1985), Sweden (Elinder et al., 1985) and the U.K. (Kazantzis et al., 1992; Kazantzis and Blanks, 1992) have shown a significant excess of lung cancer in workers exposed to cadmium and its inorganic compounds, but only the study of Stayner et al. (1992) shows clear evidence of a dose-response relationship. Moreover, in some groups heavily exposed in the past to cadmium at indoor airborne levels of about 1 mg m~, only marginal or no excess of lung cancer were observed, despite marked nephrotoxicity. Long-term carcinogenesis studies following inhalation exposure to different cadmium inorganic compounds in different laboratory rodents showed some conflicting results according to animal species. All the experiments carried out in rats demonstrated an excess of lung cancer for cadmium oxide dust, cadmium sulphide, cadmium chloride and cadmium sulfate (Glaser et al., 1990), but two experiments using cadmium oxide fumes were negative. A significant excess of lung tumours was observed in mice exposed to cadmium oxide fumes and cadmium oxide dust, but not in those exposed to cadmium sulphide (Heinrich, 1992). By contrast, all experiments following inhalation exposure in hamsters failed to demonstrate any increased occurence of lung cancer (Heinrich et al., 1989), whatever the cadmium compound. The aim of the experiment reported here was to show whether cadmium chloride (CdCl2) acted, either as a complete lung carcinogen when inhaled alone during a short exposure period at dose levels similar to that encountered in industry in a recent past, or as a lung co-carcinogen in rats previously exposed to fission neutrons, irradiation acting then as an initiator, or as a lung co-carcinogen in rats exposed to cadmium chloride and treated after the end of inhalation by intramuscular injections of 5-6 benzoflavone (PNF) which has been previously demonstrated to be a specific promotor of experimentally induced squamous cell lung cancers in Sprague-Dawley rats (Morin et al., 1978).

Stimulation of in vivo tumor growth and phorbol ester-induced inflammation by N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine HCl, a potent ligand for intracellular histamine receptors

We have implicated histamine as a mediator of proliferation through its binding to novel intracellular receptors (HIC), closely associated with antiestrogen binding sites (AEBS) in microsomes and nuclei. N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl (DPPE), is a potent ligand for AEBS/HIC. We now demonstrate that DPPE stimulates in vivo tumor growth (DMBA-induced mammary cancer in Sprague-Dawley rats and L5178Y leukemia in DBA/2 mice) and synergizes with phorbol-12-myristate-13-acetate (PMA) to induce inflammation and mitotic activity in mouse epidermis. Thus, ligands for intracellular histamine receptors may represent a new class of tumor promoting agents; this finding lends new credence to an important role for histamine in growth.

The role of histamine antagonists on the development of experimental cancer in the rat.

“The effect of the H1-receptor antagonist Diphenhydramine and the H2-receptor antagonist, Cimetidine, on the incidence, degree of histological differentiation and histological staging of 1–2 Dimethylhyd-razine (DMH) induced colonic cancer in Sprague-Dawley rats was studied. DMH was administered to 60 rats by subcutaneous injection of 20 mgs/Kg body weight per week for 16 weeks. Diphenhydramine and Cimetidine were given at a dose of 100 mgs/Kg body weight per day for 26 weeks. All rats were killed at 26 weeks and examined histologically for the presence of colonic cancer, degree of differentiation, lym-phocytic infiltration and staging. A total and a differential white cell count was examined in blood samples.

N-Nitroso-N-methylurea elicits mammary cancer in resistant and sensitive rat strains.

A single intravenous (i.v.) injection of the water-soluble mammary carcinogen N-nitroso-N-methylurea (NMU; 35 mg/kg of body weight) elicited cancer of the breast in young female rats of two strains in the following incidence: Long-Evans strain, 4%; Sprague-Dawley strain, 70%. In sisters of these rats, a set of 5 i.v. injections of NMU (35 mg/kg at biweekly intervals) evoked mammary carcinoma as follows: Long-Evans strain, 76%; Sprague-Dawley strain, 100%. In its effectiveness in evoking mammary cancer in Sprague-Dawley rats, the lipid-soluble mammary carcinogen 7,8,12-trimethylbenz[a]anthracene exceeded NMU in rapidity of development of cancer and in tumor yield.