Total Tumor Incidence Research Articles

The effects of long-term exposure to ozokerite mainly consisting of an aliphatic series of hydrocarbons using F344 rats

Combined chronic toxicity and carcinogenicity studies of ozokerite (OZK), a natural wax substance used as a food additive for a gum base, were performed in male and female F344 rats. Dietary concentrations of 0%, 0.05%, 0.1% and 0.2% OZK were applied in a 52-week chronic toxicity study and 0%, 0.1% and 0.2% in a 104-week carcinogenicity study. In the chronic toxicity study, treatment with OZK caused a xenobiotic reaction against absorbed OZK, including formation of histiocytosis and granulomas with crystalline material in many organs in all of the treated males and females. Particularly in the liver, granulomatous inflammation was accompanied by hepatocellular vacuolation and changes in the serum biochemical parameters indicative of hepatic disorder. The number and area of glutathione S-transferase placental form (GST-P) positive foci were increased in all of the treated groups of both sexes, suggesting the proliferative effect of OZK. In the carcinogenicity study, the incidence of hepatocellular adenoma and the total tumor incidence in the liver of all of the treated males were significantly increased compared with the controls. In conclusion, long-term exposure to OZK caused systemic chronic inflammation due to a foreign body response. OZK was weakly carcinogenic in the liver of male F344 rats.

Long-term treatment with l-isoleucine or l-leucine in AIN-93G diet has promoting effects on rat bladder carcinogenesis

In the present study, effects of l-leucine and l-isoleucine on rat bladder carcinogenesis were investigated using AIN-93G and MF basal diet. In Experiment 1, N-butyl-N-(4-hydroxybutyl)-nitrosamine was used as an initiator of bladder carcinogenesis. In the AIN-93G diet groups, a significantly higher incidence and multiplicity of bladder tumors, accompanied by decreased final body weight, was observed in the l-leucine-supplemented group and a significantly higher incidence of papillomas and total tumors was observed in the l-isoleucine-supplemented group. In the MF diet groups, the multiplicity of papillary and nodular hyperplasia was significantly increased in the l-isoleucine-supplemented group. Urinary pH values were not affected by supplementing either type of diet with l-leucine or l-isoleucine. In Experiment 2, the amino acid was administered in the basal diets for 2weeks without initiator. No pathological lesions were observed in the bladder urothelium in any of the groups, and no significant differences in urinary pH values, microcrystals or aggregates were observed between the amino acid-supplemented groups and their respective control groups. In conclusion, long-term treatment with l-leucine or l-isoleucine has a promoting effect on rat bladder carcinogenesis; therefore, their long-term use as a dietary supplement for bladder cancer patients should be avoided until more is known.

Induction of Ovarian Cancer and DNA Adducts by Dibenzo[a,l]pyrene in the Mouse

Tobacco smoking is an etiological factor of ovarian cacner; however, the mechanisms remain largely undefined. Therefore, as an initial investigation, we examined the carcinogenicity and DNA adducts formation in the ovary of mice treated with DB[a,l]P, a tobacco smoke constituent and environmental pollutant. Ovarian tumors in B6C3F1 mice were induced by direct application of DB[a,l]P (24, 12, 6, and 3 nmol/mouse, three times a week for 38 weeks) into the oral cavity of mice. At 6 nmol, DB[a,l]P induced the highest total ovarian tumor incidence (79%), but the incidence of malignancy was only 15%. However, at the dose of 12 nmol, the total ovarian tumor incidence was 75%, and the incidence of malignancy was 65%. In addition to ovarian tumors, at the dose of 24 nmol, DB[a,l]P induced lesions in sites distal from the ovaries including the skin, mammary, lung, and oral tissues, which were rare at doses lower than 24 nmol. Another bioassay was conducted to detect and quantify DNA adducts induced by DB[a,l]P (24 nmol, three times a week for 5 weeks) in the ovary at 48 h and 1, 2, and 4 weeks after the last administration of DB[a,l]P. DNA was isolated, and the dibenzo[a,l]pyrene-11,12-dihydrodiol-13,14-epoxide (DB[a,l]PDE)-DNA adducts were analyzed by a LC-MS/MS method. DB[a,l]P resulted in the formation of (-)-anti-cis-DB[a,l]PDE-dA and (-)-anti-trans-DB[a,l]PDE-dA adducts, which were 0.8 and 1.6 fmol/10(6) dA, respectively, in ovaries of mice within 48 h, and the level of adducts decreased over a week. Our results indicated that DB[a,l]P can be metabolized to form (-)-anti-DB[a,l]PDE; the latter may, in part, account for DB[a,l]P-induced ovarian cancer. This animal model should assist to better understand the mechanisms, account for the induction of ovarian cancer by tobacco carcinogens, and facilitate the development of chemopreventive agents against ovarian cancer.

Abstract 1333: Carcinogenicity and formation of DNA adducts induced by dibenzo[a,l]pyrene (DB[a,l]P), an environmental pollutant and a tobacco smoke component, in the ovary of mouse

Abstract Ovarian cancer ranks second among gynecologic cancers, and it is the fifth leading cause of cancer deaths among women; 13,850 deaths are expected in 2010. There is usually no obvious symptoms of early stage ovarian cancer; therefore only 15% of ovarian cancers are diagnosed in the localized stage, and the five-year survival rate for ovarian cancer patients is 46%. A positive relation of mucinous ovarian tumors to tobacco smoking had been reported; furthermore, an association was shown between mucinous ovarian cancer with ex-smokers as well. The mechanisms that can account for the role of tobacco smoking on this disease remain unknown. Currently, there is no preclinical animal model that can accurately reflect the ovarian cancer resulting from chronic exposure to chemical carcinogens present in cigarette smoke. A previous report showed that dibenzo[a,l]pyrene (DB[a,l]P) can induce ovarian cancer in mice. Therefore, in this study we examined the carcinogenicity and DNA adducts formation in the ovary of mice treated with DB[a,l]P. In carcinogenesis study, ovarian tumors in B6C3F1 mice were induced by administering DB[a,l]P into the oral cavity of mice. Several groups of B6C3F1 mice (20/group) received various doses of DB[a,l]P (24, 12, 6, and 3 nmol/mouse), and additional groups received DMSO 3 times a week for 38 weeks or were left untreated as controls. Mice were sacrificed 4 weeks after the last carcinogen administration. A short-term bioassay was also conducted to detect and quantify DNA-adducts induced by DB[a,l]P as a function of time in the ovary; mice were administered orally (24 nmol) 3 times a week for 5 weeks. Ovaries were removed from mice 48 h, 1, 2 and 4 weeks after the last dose. DNA were isolated and hydrolyzed enzymatically, and the DB[a,l]PDE-DNA adducts were analyzed by our newly developed LC-MS/MS method. At the dose of 6 nmol in carcinogenesis study, we observed the highest total ovarian tumor incidence (79%), but the incidence of malignancy was only 15%. However, at the dose of 12 nmol, the total tumor incidence was 75%, and the incidence of malignant granulosa cell tumor was 65%. In addition to ovarian tumors, we also observed lesions in sites distal from the ovaries including the skin, mammary, lung, and oral tissues at the dose of 24 nmol, which were rare in other dosing groups. Treatment of DB[a,l]P in mice resulted in the formation of (−)-anti-cis-DB[a,l]PDE-dA and (−)-anti-trans-DB[a,l]PDE-dA adducts, which were 1.6 and 3.1 fmol/µg DNA respectively in ovaries of mice within 48 hours, and the level of adducts decreased dramatically over a week. Our results indicated that DB[a,l]P can be activated to form (−)-anti-DB[a,l]PDE; the latter may account for DB[a,l]P-induced ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1333. doi:10.1158/1538-7445.AM2011-1333

Abstract 4589: Gamma-tocopherol and mixed tocopherols inhibit AOM-induced colon carcinogenesis that was promoted by moderate but not severe colon inflammation caused by dextran sodium sulfate

Abstract Our previous studies indicate that specific forms of vitamin E such as gamma-tocopherol (gT), the predominant form of vitamin E in US diets, have anti-inflammatory activities by inhibition of proinflammatory eicosanoids including prostaglandin E2 and leucotriene B4. These eicosanoids are known to promote carcinogenesis of different types of cancer including colon cancer. We therefore hypothesize that gT may be an effective anticancer agent against colon cancer. In male BALC mice, we examined potential effect of gT and mixed tocopherols at 1000mg/kg diet on AOM induced colon carcinogenesis which was promoted by 3-cycle DSS (dextrane sodium sulfate, 1.5%, 2.5% and 2%). The results show that two months after carcinogenesis was induced, all the AOM-DSS mice developed tumors located in the distal colon with ∼12 tumors per mouse. Supplementation of gT or gT-rich mixed tocopherols had no significant effects on tumor incidence or tumor size. In a subsequent study, potential effect of gT and gT rich mixed tocopherols were examined in the AOM induced colon cancer that was promoted by moderate colon inflammation caused by one-cycle 1.5% DSS. GT supplementation, although had no effects on total tumor incidence, significantly (P < 0.05) suppressed the incidence of large tumor (>2 mm2) by 60%. Mixed tocopherols showed strong tendency in attenuation of tumor development (50%, P = 0.06). Interestingly, gT but not mixed tocopherols significantly attenuated DSS-induced colon inflammation. These results indicate that gT appears to have anticancer activities via anti-inflammatory mechanisms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4589. doi:10.1158/1538-7445.AM2011-4589

One-year, simultaneous combined exposure of CDMA and WCDMA radiofrequency electromagnetic fields to rats

Purpose: We investigated whether one-year, long-term, simultaneous exposure to code division multiple access (CDMA; 849 MHz) and wideband code division multiple access (WCDMA; 1.95 GHz) radiofrequencies (RF) would induce chronic illness in Sprague-Dawley (SD) rats.Materials and methods: Two groups of 40 SD rats (50% males and females in sham and exposed groups) were exposed to CDMA and WCDMA RF simultaneously at 2.0 W/kg for 45 min/day (total 4.0 W/kg), 5 days per week for a total of one year. Body and organ weight measurements, urinalysis, haematological and blood biochemical analysis, and histopathological evaluations were performed.Results: The mortality patterns in male and female rats exposed to RF were compared with those found in gender-matched sham control animals. No significant alteration in body weight was observed with the simultaneous combined RF exposure. Most RF-exposed rats showed no significant alteration, based on urinalysis, haematology, blood biochemistry, or histopathology. However, some altered parameters of the complete blood count and serum chemistry were seen in RF-exposed rats. The total tumour incidence was not different between sham-exposed and RF-exposed animals.Conclusions: Our results suggest that one-year chronic exposure to CDMA (849 MHz) and WCDMA (1.95 GHz) RF simultaneously at 2.0 W/kg for 45-min RF exposure periods (total, 4 W/kg) did not increase chronic illness in rats, although there were some altered parameters in the complete blood count and serum chemistry.

Behandlung differenzierter Schilddrüsenkarzinome bei Kindern und Jugendlichen

Schilddrüsenkarzinome im Kindes- und Jugendalter sind zu etwa 10% an der Gesamtinzidenz maligner Schilddrüsentumoren beteiligt. Kindliche Schilddrüsen sind sehr strahlensensibel; Deswegen ist das Risiko für die Induktion von Schilddrüsenkarzinomen durch ionisierende Strahlung insbesondere bei Kleinkindern deutlich erhöht. Im Gegensatz zu Erwachsenen korreliert der Schweregrad der Erkrankung beim kindlichen Schilddrüsenkarzinom negativ mit dem Alter, d. h. die Verläufe sind von der lokalen Ausbreitung sowie der Metastasierung her umso aggressiver, je jünger die Kinder sind. Bei Kindern und Jugendlichen überwiegt die papilläre Form des Schilddrüsenkarzinoms eindeutig. Lymphknotenmetastasen im Halsbereich finden sich in ca. der Hälfte der Fälle; Fernmetastasen (vorwiegend in der Lunge) bei etwa einem Viertel der Patienten. In der Regel wird das Schilddrüsenkarzinom im Kindes- und Jugendalter sonografisch diagnostiziert; typisches Merkmal ist der echoarme Knoten. Allerdings gibt es auch die diffuse, das ganze Organ infiltrierende Form des Schilddrüsenkarzinoms im Kindesalter. Für das Tumorstaging und die Einteilung in Risikogruppen eignet sich das von der UICC für Erwachsene vorgeschlagene Klassifikationsschema nicht. Die Standardtherapie des Schilddrüsenkarzinoms besteht aus der totalen Thyreoidektomie und Lymphknotenausräumung im medianen Halskompartment sowie der postoperativen Radioiodtherapie mit anschließender TSH-suppressiver Levothyroxinsubstitution. Kinder benötigen im Allgemeinen höhere Levothyroxin-dosen pro kg KG als Erwachsene. Die Ergebnisse der Therapie des differenzierten Schilddrüsenkarzinoms bei Kindern und Jugendlichen sind als ausgezeichnet zu bezeichnen; die 10-Jahres-Überlebensraten liegen bei nahezu 100%. Eine multivariate Analyse zeigt, dass die radikale Thyreoidektomie und die postoperative Radioiodtherapie unabhängige, signifikante Erfolgsfaktoren im Hinblick auf die Vermeidung lokoregionaler Rezidive sind. Bei der Radioiodbehandlung von Kindern und Jugendlichen mit Lungenmetastasen ist auf das Risiko einer strahleninduzierten Lungenfibrose zu achten. In einem nicht unerheblichen Prozentsatz der Fälle kommt es auch bei nicht vollständiger Elimination der Lungenmetastasen in der Ganzkörperszintigrafie zu einem kontinuierlichen Abfall der Serumthyreoglobulinspiegel im Sinne lang andauernder Teilremissionen.

Chronic exposure of Sprague-Dawley rats to 20 kHz triangular magnetic fields

Purpose: As a continuing study of 20 kHz triangular magnetic fields (MF) [Lee et al. ], we investigated the chronic toxicity and possible health effects of exposure to 20 kHz MF at the flux density of 30 μT, which is the limit standard for the occupational population in South Korea, with the use of Sprague-Dawley rats.Materials and methods: Rats were exposed to 20 kHz triangular MF at 30 μT Root Mean Square for 8 h/day for 18 months. Body and organ weights were measured and urinalysis, hematological and blood biochemistry analyses were performed in individual animals. Histopathological evaluation was also performed for the brain, thymus, lung, heart, liver, kidney, intestine and reproductive organs, including tumour tissue.Results: The mortality patterns in male or female rats exposed to magnetic fields were compared to the mortality patterns found in sex-matched sham control animals. Significant alteration of body weight was not observed with MF exposure. No significant differences were seen in sham-exposed and MF-exposed animals based on urological factors, hematological factors and blood biochemistry. Total tumour incidence was not different between sham-exposed and MF-exposed animals.Conclusion: Our results suggest that chronic exposure to 20 kHz triangular MF with 30 μT flux density did not increase toxicity in rats.

Anticarcinogenic efficacy of phytic acid extracted from rice bran on azoxymethane-induced colon carcinogenesis in rats

This study is carried out to determine the potential of phytic acid extracted from rice bran in the suppression of colon carcinogenesis induced by azoxymethane (AOM) in rats. Seventy-two male Sprague-Dawley rats were divided into 6 groups with 12 rats in each group. The intended rats for cancer treatment received two intraperitoneal injections of AOM in saline (15mg/kg bodyweight) over a 2-week period. The treatments of phytic acid were given in two concentrations: 0.2% (w/v) and 0.5% (w/v) during the post-initiation phase of carcinogenesis phase via drinking water. The colons of the animals were analyzed for detection and quantification of aberrant crypt foci (ACF) after 8 weeks of treatment. The finding showed treatment with 0.2% (w/v) extract phytic acid (EPA) gave the greatest reduction in the formation of ACF. In addition, phytic acid significantly suppressed the number of ACF in the distal, middle and proximal colon as compared to AOM alone (p<0.05). For the histological classification of ACF, treatment with 0.5% (w/v) commercial phytic acid (CPA) had the highest percentage (71%) of non-dysplastic ACF followed by treatment with 0.2% (w/v) EPA (61%). Administration of phytic acid also reduced the incidence and multiplicity of total tumors even though there were no significant differences between groups. In conclusion, this study found the potential value of phytic acid extracted from rice bran in reducing colon cancer risk in rats.

A Cohort Study of Childhood Cancer Incidence after Postnatal Diagnostic X-Ray Exposure

Ionizing radiation is an established cause of cancer, yet little is known about the health effects of doses from diagnostic examinations in children. The risk of childhood cancer was studied in a cohort of 92.957 children who had been examined with diagnostic X rays in a large German hospital during 1976-2003. Radiation doses were reconstructed using the individual dose area product and other exposure parameters, together with conversion coefficients developed specifically for the medical devices and standards used at the radiology department. Newly diagnosed cancers occurring between 1980 and 2006 were determined through record linkage to the German Childhood Cancer Registry. The median radiation dose was 7 microSv. Eight-seven incident cases were found in the cohort: 33 leukemia, 13 lymphoma, 10 central nervous system tumors, and 31 other tumors. The standardized incidence ratio (SIR) for all cancers was 0.99 (95% CI: 0.79-1.22). No trend in the incidence of total cancer, leukemia or solid tumors with increasing radiation dose was observed in the SIR analysis or in the multivariate Poisson regression. Risk did not differ significantly in girls and boys. Overall, while no increase in cancer risk with diagnostic radiation was observed, the results are compatible with a broad range of risk estimates.

The induction of insulinomas by X-irradiation to the gastric region in Otsuka Long-Evans Tokushima Fatty rats

The X-ray induction of tumors was examined in five-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, treated with two 10 Gy doses to the gastric region with a 3-day interval (total 20 Gy). After irradiation, the rats received the commercial diet MF and tap water and were maintained for up to 564 days. The mean serum glucose level in the X-irradiated group was significantly lower than that in the non-irradiated animals at the 18 month time point. The total tumor incidence was 27/30 (87.1%) in the treated rats (islet tumors, gastric tumors, sarcomas, seminomas, adrenal tumors, kidney tumors, papilloma, lymphomas and mammary tumors). Islet tumors, generally showed to be positive for insulin by immunohistochemistry, developed in 19 rats (63.3%), and were associated with low serum glucose. Since spontaneous tumors observed in 6/19 (31.6%) rats (sarcomas, kidney tumors, duodenum tumors, seminoma, adrenal tumor and squamous cell carcinoma) did not include any insulinomas, these are clearly induced by X-irradiation in OLETF rats.

Lack of carcinogenicity of lyophilized Agaricus blazei Murill in a F344 rat two year bioassay

The Brazilian mushroom Agaricus blazei Murill has antimutagenic, antioxidant, immunostimulatory and antitumorigenic activities, and is increasingly consumed as a health food worldwide. We undertook the present study to evaluate the chronic toxicity and oncogenicity of A. blazei Murill in F344 rats. To establish a no-observed-adverse-effect level (NOAEL), four treatment groups of 100 rats each (50 males and 50 females) were fed a powder diet containing lyophilized A. blazei aqueous extract at 0, 6250, 12,500, and 25,000 ppm for up to 2 years. During this period, there was no remarkable change in mean body weight, body weight gain, hematologic or serum chemistry parameters, or absolute or relative organ weights in control or treatment groups. Mortality in male treatment groups (26%, 16%, and 30%), however, was significantly lower than in controls (48%). Histopathological studies showed no increased incidence of tumors in any treatment group, and total tumor incidence across all groups was comparable to historical data. In conclusion, an A. blazei Murill lyophilized powder diet even at 25,000 ppm (1176 mg/kg b.w./day for male rats and 1518 mg/kg b.w./day for female rats) resulted in no remarkable carcinogenic effects in F344 rats over a 2-year period. Therefore, the dietary NOAEL is 25,000 ppm.

Lack of Urinary Bladder Carcinogenicity of Sodium L-Ascorbate in Human c-Ha-ras Proto-Oncogene Transgenic Rats

Sodium L-ascorbate (Na-AsA) is widely known to be a tumor promoter of rat bladder carcinogenesis but tests negative in standard 2-year bioassays. In the present study, bladder-cancer-susceptible transgenic rats designated Hras128 were used to further examine the tumorigenicity of Na-AsA. A total of 40 7-week-old male transgenic (Tg) and 42 littermate nontransgenic (Non-tg) rats were divided into 4 groups and given powdered MF diet with or without 5% Na-AsA for 57 weeks. Tg rats showed significantly short survival compared with Non-tg, independent of Na-AsA treatment. Tg rats treated with Na-AsA showed a slightly higher incidence of carcinoma (29.6%) as compared to those without Na-AsA treatment (15.4%), but this was without statistical significance. Moreover, the total bladder tumor incidences, including papillomas, did not differ statistically (with Na-AsA, 37.0%; without Na-AsA, 30.8%). No bladder tumor was detected in Non-tg rats. Various kinds of other lesions in various organs were noted in Tg rats treated with or without Na-AsA treatment, but no intergroup differences were evident. In conclusion, Na-AsA did not show tumorigenicity in highly bladder-cancer-susceptible transgenic Hras128 rats. These results suggest that Na-AsA is a pure promoter but not a complete carcinogen in rats.

A Toxicogenomics Approach to Identify New Plausible Epigenetic Mechanisms of Ochratoxin A Carcinogenicity in Rat

Ochratoxin A (OTA) is a mycotoxin occurring naturally in a wide range of food commodities. In animals, it has been shown to cause a variety of adverse effects, nephrocarcinogenicity being the most prominent. Because of its high toxic potency and the continuous exposure of the human population, OTA has raised public health concerns. There is significant debate on how to use the rat carcinogenicity data to assess the potential risk to humans. In this context, the question of the mechanism of action of OTA appears of key importance and was studied through the application of a toxicogenomics approach. Male Fischer rats were fed OTA for up to 2 years. Renal tumors were discovered during the last 6 months of the study. The total tumor incidence reached 25% at the end of the study. Gene expression profile was analyzed in groups of animals taken in intervals from 7 days to 12 months. Tissue-specific responses were observed in kidney versus liver. For selected genes, microarray data were confirmed at both mRNA and protein levels. In kidney, several genes known as markers of kidney injury and cell regeneration were significantly modulated by OTA. The expression of genes known to be involved in DNA synthesis and repair, or genes induced as a result of DNA damage, was only marginally modulated. Very little or no effect was found amongst genes associated with apoptosis. Alterations of gene expression indicating effects on calcium homeostasis and a disruption of pathways regulated by the transcription factors hepatocyte nuclear factor 4 alpha (HNF4alpha) and nuclear factor-erythroid 2-related factor 2 (Nrf2) were observed in the kidney but not in the liver. Previous data have suggested that a reduction in HNF4alpha may be associated with nephrocarcinogenicity. Many Nrf2-regulated genes are involved in chemical detoxication and antioxidant defense. The depletion of these genes is likely to impair the defense potential of the cells, resulting in chronic elevation of oxidative stress in the kidney. The inhibition of defense mechanism appears as a highly plausible new mechanism, which could contribute to OTA carcinogenicity.

Dose‐dependence of promotion of 2‐amino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline‐induced rat hepatocarcinogenesis by ethanol: Evidence for a threshold

Although ethanol is thought to be a tumor-promoter, there are conflicting results concerning its effects on experimental hepatocarcinogenesis. Furthermore, the relationship between the amount of ethanol consumed and tumor promoting effects has hitherto not been investigated in detail. In the present study, 21-day-old F344/DuCrj rats were fed 200 p.p.m. 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in their diet for 8 weeks and thereafter received ethanol at doses of 0, 0.1, 0.3, 1, 3, 10 and 20% in drinking water ad libitum for 16 weeks. The incidences of hepatocellular adenoma and total tumors increased dose-dependently with statistical significance at doses of 10% and 20%, compared to the initiated control value. Similarly, dose dependence was observed for the incidence of hepatocellular carcinoma, which was elevated significantly at the dose of 20%. No alteration in development of preneoplastic glutathione-S-transferase placental form positive foci or tumors was observed with 0.1-1%. Cell proliferation also increased dose-dependently and CYP2E1 protein induction was recognized in centrilobular regions without alteration in mRNA levels, but no effects were evident on formation of 8-hydroxy-2'-deoxyguanosine, an oxidative DNA damage marker, or lipid peroxidation in any of the initiated groups. The mRNA expression of cyclin D1 increased dose dependently. The results demonstrated that ethanol dose-dependently promotes hepatocarcinogenesis induced by MeIQx, but with no adverse influence at doses of 1% or less, comparable to sensible drinking levels in humans.

Metallothionein-I/II Double Knockout Mice Are No More Sensitive to the Carcinogenic Effects of Nickel Subsulfide than Wild-Type Mice

Metallothionein (MT) is a high-affinity metal-binding protein thought to mitigate the toxicity of various metals. MT may limit the toxicity of a metal by direct binding or through action as an antioxidant for metals that generate reactive oxygen species. Nickel compounds have carcinogenic potential in humans and animals, possibly by production of oxidative stress. The impact of MT deficiency on the carcinogenic effects of nickel is unknown. Thus, groups (n=25) of male MT-I/II double knockout (MT-null) or MT wild-type (WT) mice were exposed to a single treatment of nickel (0.5 or 1.0 mg Ni3S2/site, intramuscularly, [i.m.], into both hind legs), or left untreated (control) and observed over the next 104 weeks. There were no differences in the incidence of spontaneous tumors in MT-null and WT mice. Nickel induced injection site fibrosarcomas in a dose-related fashion to a similar extent in both WT and MT-null mice. Nickel-treatment had no effect on total lung tumor incidence, although some phenotypic-specific differences occurred in the proportion of benign and malignant pulmonary tumors. Overall, MT-null mice appear no more sensitive to the carcinogenic effects of nickel than WT mice. Thus, poor MT production does not appear to be a predisposing factor for nickel carcinogenesis.

Down-regulation of SNAIL suppresses MIN mouse tumorigenesis: Modulation of apoptosis, proliferation, and fractal dimension

Emerging evidence implicates the SNAIL family of transcriptional repressors in cancer development; however, the role of SNAIL in colorectal cancer has not been established. To investigate the importance of SNAIL in colorectal carcinogenesis, we examined the phenotypic and cellular consequences of SNAIL down-regulation in the MIN mouse. Twenty-eight male MIN mice were randomized to treatment with an antisense phosphorodiamidate morpholino oligomer (AS-PMO) to SNAIL, saline, or a scrambled sequence control for 6 weeks. Tumors were scored and the molecular/cellular effects of anti-SNAIL treatment were evaluated through immunohistochemical analysis of the uninvolved intestinal mucosa for SNAIL and E-cadherin levels along with rates of apoptosis and proliferation. Furthermore, microarchitectural alterations were determined through measurement of fractal dimension. In the uninvolved mucosa, SNAIL AS-PMO treatment moderately decreased SNAIL protein when compared with saline-treated animals (immunohistochemistry scores 3.0 +/- 0.8 versus 2.1 +/- 0.6, respectively; P=0.01) with a concomitant increase in E-cadherin expression (1.8 +/- 0.6 versus 2.4 +/- 0.5; P < 0.05). Anti-SNAIL PMO, but not scramble control, resulted in a significant decrease in both total tumor number and incidence of tumors >2 mm (22% and 54%, respectively; P < 0.05). Furthermore, this was accompanied by an increased apoptosis rate (2-fold), decreased proliferation (3-fold), and normalization of the fractal dimension in the uninvolved intestinal mucosa. We show, for the first time, that SNAIL overexpression is important in intestinal tumorigenesis. While this PMO regimen afforded modest SNAIL suppression and hence tumor reduction, this provides compelling evidence for the role of SNAIL overexpression in colonic neoplasia.

Spontaneous Tumors in Hypocatalasemic C3H/ C&lt;sup&gt;b&lt;/sup&gt;&lt;sub&gt;s&lt;/sub&gt; /Gen and C3H Mice

Hypocatalasemic mice (Cbs) were examined for their life span and compared to C3H mice with reference to oxidase enzyme activity and spontaneous tumor development. N1-methylnicotinamice oxidase, xanthine oxidase (XO), xanthine dehydrogenase (XDH), and XO+XDH activities in 8 week-old male Cbs mice were decreased as compared to the C3H counterparts. On the other hand, benzaldehyde oxidase in both sexes and xanthine dehydrogenase activity in females were significantly elevated as compared to the C3H. The total tumor incidence, number of tumors per mouse, liver tumors, and other tumor induction were significantly greater in as compared with until 499 days group in both sexes (P<0.01). The total incidence of tumors and incidence of liver tumors were not significantly different between the two strains in both sexes. The number of tumors per animal in C3H females and incidence of sarcoma in both sexes were significantly decreased as compared with the Cbs case but the numbers of liver tumor per animal and ovarian tumors were significantly greater.

Effect of delta-sleep inducing peptide-containing preparation Deltaran on biomarkers of aging, life span and spontaneous tumor incidence in female SHR mice

From the age of 3 months until their natural deaths, female Swiss-derived SHR mice were subcutaneously injected 5 consecutive days every month with 0.1 ml of normal saline (control) or with 2.5 μg/mouse (∼100 μg/kg) of delta-sleep inducing peptide (DSIP, Trp–Ala–Gly–Gly–Asp–Ala–Ser–Gly–Glu) as the preparation Deltaran ® solved in 0.1 ml of saline. There were 54 mice in each group. The results of this study show that the treatment with Deltaran did not influence food consumption, but decreased the body weight of mice; it slowed down the age-related switching-off of estrous function; it decreased by 22.6% the frequency of chromosome aberrations in bone marrow cells; it did not influence mean life span; and it increased by 17.1% life span of the last 10% of the survivors and by 24.1% maximum life span in comparison with the control group. We also found that treatment with Deltaran significantly decreased total spontaneous tumor incidence (by 2.6-fold), mainly mammary carcinomas and leukemias in mice as compared with the control group. This is the first report on geroprotector and anticarcinogenic effect of DSIP-containing preparation Deltaran.

Effect of Epitalon on biomarkers of aging, life span and spontaneous tumor incidence in female Swiss-derived SHR mice.

From the age of 3 months until their natural deaths, female outbred Swiss-derived SHR mice were subcutaneously injected on 5 consecutive days every month with 0.1 ml of normal saline (control) or with 1.0 microg/mouse (approximately 30-40 microg/kg) of tetrapeptide Epitalon (Ala-Glu-Asp-Gly) dissolved in 0.1 ml saline. There were 54 mice in each group. The results of this study show that treatment with Epitalon did not influence food consumption, body weight or mean life span of mice. However, it slowed down the age-related switching-off of estrous function and decreased the frequency of chromosome aberrations in bone marrow cells (by 17.1%, P<0.05). It also increased by 13.3% the life span of the last 10% of the survivors (P<0.01) and by 12.3% the maximum life span in comparison with the control group. We also found that treatment with Epitalon did not influence total spontaneous tumor incidence, but inhibited the development of leukemia (6.0-fold), as compared with the control group. The data obtained suggest a geroprotector activity of Epitalon and the safety of its long-term administration in mice.