Effects of bisphenol A on murine salivary glands and human tumor cell lines.

Bisphenol A (BPA) is an endocrine-disrupting chemical with a potential role in endocrine cancers. However, the effects of BPA on the salivary glands have been barely explored. We investigated the impact of in vivo sub-chronic exposure to BPA and its in vitro effects on human salivary gland mucoepidermoid carcinoma cell lines. Male and female mice were exposed to BPA (30 mg/kg/day). Sublingual and submandibular salivary glands from an estrogen-deficiency model were also analyzed. BPA concentration in salivary glands was evaluated by gas chromatography coupled to ion trap mass spectrometry. Immunohistochemical analysis using anti-p63 and anti-α-SMA antibodies was performed on mouse salivary gland tissues. Gene expression of estrogen receptors alpha and beta, P63 and α-SMA was quantified in mouse salivary gland and/or mucoepidermoid (UM-HMC-1 and UM-HMC-3A) cell lines. Cell viability, p63 and Ki-67 immunostaining were evaluated in vitro. BPA disrupted the tissue architecture of the submandibular and sublingual glands, particularly in female mice, and increased the expression of estrogen receptors and p63, effects that were accompanied by significant BPA accumulation in these tissues. Conversely, ovariectomy slightly impacted BPA-induced morphological changes. In vitro, BPA did not affect the proliferation of neoplastic cells, but augmented the expression of p63 and estrogen receptors. The present data highlight a potential harmful effect of BPA on salivary gland tissues, particularly in female mice, and salivary gland tumor cells. Our findings suggest that estrogen-dependent pathways may orchestrate the effects of BPA in salivary glands.

Nivolumab plus ipilimumab in advanced salivary gland cancer: a phase 2 trial.

Salivary gland cancers (SGCs) are rare, aggressive cancers without effective treatments when metastasized. We conducted a phase 2 trial evaluating nivolumab (nivo, anti-PD-1) and ipilimumab (ipi, anti-CTLA-4) in 64 patients with metastatic SGC enrolled in two histology-based cohorts (32 patients each): adenoid cystic carcinoma (ACC; cohort 1) and other SGCs (cohort 2). The primary efficacy endpoint (≥4 objective responses) was met in cohort 2 (5/32, 16%) but not in cohort 1 (2/32, 6%). Treatment safety/tolerability and progression-free survival (PFS) were secondary endpoints. Treatment-related adverse events grade ≥3 occurred in 24 of 64 (38%) patients across both cohorts, and median PFS was 4.4 months (95% confidence interval (CI): 2.4, 8.3) and 2.2 months (95% CI: 1.8, 5.3) for cohorts 1 and 2, respectively. We present whole-exome, RNA and T cell receptor (TCR) sequencing data from pre-treatment and on-treatment tumors and immune cell flow cytometry and TCR sequencing from peripheral blood at serial timepoints. Responding tumors universally demonstrated clonal expansion of pre-existing T cells and mutational contraction. Responding ACCs harbored neoantigens, including fusion-derived neoepitopes, that induced T cell responses ex vivo. This study shows that nivo+ipi has limited efficacy in ACC, albeit with infrequent, exceptional responses, and that it could be promising for non-ACC SGCs, particularly salivary duct carcinomas. ClinicalTrials.gov identifier: NCT03172624 .

A Single-Arm, Prospective, Phase II Study of Cisplatin Plus Weekly Docetaxel as First-Line Therapy in Patients with Metastatic or Recurrent Salivary Gland Cancer.

PURPOSE: Salivary gland cancers (SGCs) are relatively rare but comprise various histologic subtypes, which complicates design of prospective trials. Systemic chemotherapy plays a limited role in treatment of SGCs, but cisplatin and docetaxel showed efficacy in a previous preclinical study. Here, we conduct a prospective, phase II study to evaluate the efficacy and toxicities of cisplatin plus weekly docetaxel in patients with metastatic or recurrent SGC. MATERIALS AND METHODS: We included patients with histologically confirmed SGCs of the following subtypes: mucoepidermoid carcinoma, adenocarcinoma, ductal carcinoma, or adenoid cystic carcinoma. Patients had no prior systemic chemotherapy for metastatic or recurrent tumors and at least one measurable lesion. Patients were treated with docetaxel 35 mg/m2 (D1, 8) and cisplatin 70 mg/m2 (D1) every 21 days. RESULTS: Forty-one patients were enrolled between April 2014 and October 2020. The median age was 58 years (range, 32 to 73 years). The most common histologic subtype was adenoid cystic carcinoma (63.4%), followed by ductal carcinoma (24.4%). The most common metastatic site was the lung (75.6%). The median treatment cycle was 5.5 (range, 3 to 8), and the objective response rate was 46.3%, with three complete responses. The median duration of response was 6.8 months (interquartile range, 4.0 to 10.2). The progression-free survival and overall survival were 9.4 months (95% confidence interval [CI], 8.4 to 10.5) and 28.2 months (95% CI, 22.7 to 33.6), respectively. There were no treatment-related deaths. The most common grade 3/4 adverse events were neutropenia (4.9%) and fatigue (4.9%). CONCLUSION: Cisplatin plus weekly docetaxel is effective and tolerable with manageable toxicity as first-line therapy in patients with metastatic or recurrent SGC.

Agent Orange exposure and cancer incidence in Korean Vietnam veterans: a prospective cohort study.

BACKGROUND: During the Vietnam War, US and allied military sprayed approximately 77 million liters of tactical herbicides including Agent Orange, contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. To the authors' knowledge, few studies to date have examined the association between Agent Orange exposure and cancer incidence among Korean veterans who were exposed to Agent Orange during the Vietnam War. METHODS: An Agent Orange exposure index, based on the proximity of the veteran's military unit to the area that was sprayed with Agent Orange, was developed using a geographic information system-based model. Cancer incidence was followed for 180,251 Vietnam veterans from 1992 through 2003. RESULTS: After adjustment for age and military rank, high exposure to Agent Orange was found to significantly increase the risk of all cancers combined (adjusted hazards ratio [aHR], 1.08). Risks for cancers of the mouth (aHR, 2.54), salivary glands (aHR, 6.96), stomach (aHR, 1.14), and small intestine (aHR, 2.30) were found to be significantly higher in the high-exposure group compared with the low-exposure group. Risks for cancers of all sites combined (aHR, 1.02) and for cancers of the salivary glands (aHR, 1.47), stomach (aHR, 1.03), small intestine (aHR, 1.24), and liver (aHR, 1.02) were elevated with a 1-unit increase in the exposure index. CONCLUSIONS: Exposure to Agent Orange several decades earlier may increase the risk of cancers in all sites combined, as well as several specific cancers, among Korean veterans of the Vietnam War, including some cancers that were not found to be clearly associated with exposure to Agent Orange in previous cohort studies primarily based on Western populations.

Occurrence of salivary gland tumours in two patients treated with biological agents.

We report two cases of salivary gland tumors arising in two psoriatic patients treated with an anti- TNF-alpha agent. A clear causal relationship could not be established, but the exceptional onset of a bilateral Warthin's tumor in one of these patients should be emphasized.

Subchronic toxicity and genotoxicity of diiodomethyl-p-tolylsulfone (DIMPTS) in laboratory animals.

These studies were conducted to determine subchronic toxicity and genotoxicity of the biocide diiodomethyl-p-tolysulfone (DIMPTS) in rats and dogs. Male and female Sprague-Dawley rats and Beagle dogs were administered DIMPTS for 90-days via the diet at 0, 5, 20, and 80 mg/kg/day to rats and via capsules at 0, 2, 10, and 60 mg/kg/day to dogs. In rats, the only treatment-related finding was squamous metaplasia of the salivary gland duct in the 80 mg/kg/day group. In dogs, female body weights in the high-dose group were significantly lower than controls. Altered clinical pathology parameters were considered secondary to inflammatory changes observed in some of the dogs. Treatment-related alterations were found in the thyroid glands, salivary glands, GI-tract in the mid- and/or high-dose groups. DIMPTS was negative in the four in vitro and one in vivo genotoxicity assays. The toxicological effects noted in the two mammalian species are consistent with the principal toxic effects of iodine, and are proposed to arise from release of iodide from the DIMPTS molecule with toxic sequelae.

Recurrent bronchial epithelial-myoepithelial carcinoma after local therapy.

We present a rare case of recurrent multiple lesions of bronchial epithelial-myoepithelial carcinoma in a 74-year-old man treated with local resection. Two cellular types were found: epithelial cells and myoepithelial cells. The patient remains asymptomatic at 4-years of follow-up, supporting the fact that epithelial-myoepithelial carcinoma is a tumor of low-grade malignancy.

Influence of diets varying in lipid and protein content on the histopathologic variety of murine salivary gland tumors induced by 9,10-dimethyl-1,2-benzanthracene (DMBA).

The purpose of this study was to analyze the influence of diets varying in lipids and proteins on the histopathologic variety of murine salivary tumors induced by DMBA. 117 BALB/c mice were assigned to experiments one (E1: lipids, males) and two (E2: proteins, males and females), E1 comprising Soy oil (SO); Corn oil (CO, control); Fish oil (FO) and Olein (O) groups and E2, soy protein (SP) and casein (C) groups. Tumors were induced by DMBA and the animals were sacrificed at week 13- post-induction. Tumor volume was calculated. Tumor sections were stained with H-E for histopathologic evaluation. No significant association was found between tumor volume and dietary condition (p > 0.05). In E1, FO animals developed mainly carcinomas (C) (58.8%), the sarcomas (S) and carcinosarcomas (CS) being especially of high-grade type (tumors < 600 mm3). In E2, SP animals developed mainly C (55.6%). Although no significantly different (p > 0.05), S and C were more frequent in female and male mice, respectively. In both E1 and E2, the biggest tumors (> 600 mm3) were mainly high-grade S (87.5%-80%). Dietary fat and soy protein appear to influence the tumor histopathology and thus its prognosis.

Influence of diets varying in lipid and protein content on the histopathologic variety of murine salivary gland tumors induced by 9, 10-dimethyl-1, 2-benzanthracene (DMBA) / Influencia de dietas de diferente contenido lipídico y proteico sobre variantes histopatológicas de tumores de glándulas salivares murinos inducidos con 9, 10-dimethyl-1, 2-benzathraceno (DMBA)

The purpose of this study was to analyze the influence of diets varying in lipids and proteins on the histopathologic variety of murine salivary tumors induced by DMBA. 117 BALB/c mice were assigned to experiments one (E1: lipids, males) and two (E2: proteins, males and females), E1 comprising Soy oil (SO); Corn oil (CO, control); Fish oil (FO) and Olein (O) groups and E2, soy protein (SP) and casein (C) groups. Tumors were induced by DMBA and the animals were sacrificed at week 13- post-induction. Tumor volume was calculated. Tumor sections were stained with H-E for histopathologic evaluation. No significant association was found between tumor volume and dietary condition (p > 0.05). In E1, FO animals developed mainly carcinomas (C) (58.8%), the sarcomas (S) and carcinosarcomas (CS) being especially of high-grade type (tumors < 600 mm3). In E2, SP animals developed mainly C (55.6%). Although no significantly different (p > 0.05), S and C were more frequent in female and male mice, respectively. In both E1 and E2, the biggest tumors (> 600 mm3) were mainly high-grade S (87.5%-80%). Dietary fat and soy protein appear to influence the tumor histopathology and thus its prognosis.

El objetivo de este estudio fue analizar la influencia de dietas con diferente contenido de lípidos y proteínas sobre la variedad histopatológica de tumores salivares murinos inducidos por DMBA. Se asignaron 117 ratones BALB/c a los experimentos uno (E1: lípidos, machos) y dos (E2: proteínas, machos y hembras). E1 comprendió a los grupos aceite de soja (AS), aceite de maíz (AM, control), aceite de pescado (AP) y oleína (O), en tanto E2 incluyó a los grupos preteína de soja (PS) y caseína (C). Los tumores fueron inducidos por DMBA y los animales fueron sacrificados a la 13ª semana post-inducción. Se calculó el volumen tumoral. Los cortes de tumor fueron coloreados con Hematoxilina-Eosina para su evaluación histopatológica. No se encontró asociación entre volumen tumoral y condición dietaria (p>0.05). En E1, los animales del grupo AP desarrollaron principales carcinomas (C) (58,8%), en tanto que los sarcomas (S) y carcinosarcomas (CS) fueron de alto grado (tumores<600 mm³). En el E2, los animales del grupo PS desarrollaron principalmente C (55.6%). Aunque la diferencia no fue significativa (p>0.05), S y C fueron más frecuentes en ratones hembras y machos, respectivamente. Tanto el E1 com en E2, los tumores más voluminosos (> 600 mm³) fueron principalmente de alto grado (87.5%-80%) Los lípidos y la proteína de soja de la dieta parecen influenciar la histopatología de los tumores y, en consecuencia, su pronóstico.

Early phenotypic and genotypic alterations in submandibular gland oncogenesis in rats

Se evaluaron modificaciones del fenotipo y genotipo en glándulas submandibulares durante el desarrollo temprano de la tumorogénesis. Glándulas submandibulares de ratas macho fueron inyectadas con una solución de 0.5 por ciento de 9,10 dimetil 1,2-benzathracene (DMBA) diluida en acetona. Muestras de glándulas fueron analizadas mediante técnicas histológicas, bioquímicas, inmunocitoquímicas y por PCR a los 0, 7, 30 y 150 días postinyección. Para los estudios histopatológicos se utilizó la técnica de hematoxilina-eosina. Se determinó la concentración de proteínas totales por el método de Lowry y se realizaron corridas electroforéticas en gel de poliacrilamida SDS-PAGE al 12 por ciento para determinar el perfil proteico. Se realizó inmunomarcación para Bcl-2 con oro coloidal-plata y para p53 por streptavidina-biotina. Todos los animales tratados desarrollaron cambios similares a carcinomas a los 30 y 150 días. La concentracióan de proteínas totales aumentó significativamente (p<0,05) a los 7, 30 y 150 días en relación a los controles. En glándulas inducidas la inmunomarcación fue positiva para la proteína p53 en núcleos de células neoplásicas a los 30 y 150 días. En las mismas glándulas, la marcación citoplasmática de Bcl-2 fue positiva a los 7, 30 y 150 días(p=0,0015) y en relación a los controles (p<0,0001). No se observaron mutaciones de p53, mientras que se observó una mutación puntual, C A del gen bcl-2 a los 7, 30 y 150 días que generó un cambio de aminoácidos en la proteína (thre asn). Nuestros resultados sugieren que los cambios histopatológicos tempranos corresponden a modificaciones cuantitativas y cualitativas de las proteínas. Las modificaciones observadas a nivel histopatológico, bioquímico, inmunocitoquímico y genético en la carcinomgénesis experimental de glándula submandibular de rata podrían representar parámetros reproducibles de transformaciones malignas transferibles al ser humano, dada la alta homología de estos oncogenes entre rata, ratones...(AU)

Early phenotypic and genotypic alterations in submandibular gland oncogenesis in rats

Se evaluaron modificaciones del fenotipo y genotipo en glándulas submandibulares durante el desarrollo temprano de la tumorogénesis. Glándulas submandibulares de ratas macho fueron inyectadas con una solución de 0.5 por ciento de 9,10 dimetil 1,2-benzathracene (DMBA) diluida en acetona. Muestras de glándulas fueron analizadas mediante técnicas histológicas, bioquímicas, inmunocitoquímicas y por PCR a los 0, 7, 30 y 150 días postinyección. Para los estudios histopatológicos se utilizó la técnica de hematoxilina-eosina. Se determinó la concentración de proteínas totales por el método de Lowry y se realizaron corridas electroforéticas en gel de poliacrilamida SDS-PAGE al 12 por ciento para determinar el perfil proteico. Se realizó inmunomarcación para Bcl-2 con oro coloidal-plata y para p53 por streptavidina-biotina. Todos los animales tratados desarrollaron cambios similares a carcinomas a los 30 y 150 días. La concentracióan de proteínas totales aumentó significativamente (p<0,05) a los 7, 30 y 150 días en relación a los controles. En glándulas inducidas la inmunomarcación fue positiva para la proteína p53 en núcleos de células neoplásicas a los 30 y 150 días. En las mismas glándulas, la marcación citoplasmática de Bcl-2 fue positiva a los 7, 30 y 150 días(p=0,0015) y en relación a los controles (p<0,0001). No se observaron mutaciones de p53, mientras que se observó una mutación puntual, C A del gen bcl-2 a los 7, 30 y 150 días que generó un cambio de aminoácidos en la proteína (thre asn). Nuestros resultados sugieren que los cambios histopatológicos tempranos corresponden a modificaciones cuantitativas y cualitativas de las proteínas. Las modificaciones observadas a nivel histopatológico, bioquímico, inmunocitoquímico y genético en la carcinomgénesis experimental de glándula submandibular de rata podrían representar parámetros reproducibles de transformaciones malignas transferibles al ser humano, dada la alta homología de estos oncogenes entre rata, ratones...(AU)

Early phenotypic and genotypic alterations in submandibular gland oncogenesis in rats

Se evaluaron modificaciones del fenotipo y genotipo en glándulas submandibulares durante el desarrollo temprano de la tumorogénesis. Glándulas submandibulares de ratas macho fueron inyectadas con una solución de 0.5 por ciento de 9,10 dimetil 1,2-benzathracene (DMBA) diluida en acetona. Muestras de glándulas fueron analizadas mediante técnicas histológicas, bioquímicas, inmunocitoquímicas y por PCR a los 0, 7, 30 y 150 días postinyección. Para los estudios histopatológicos se utilizó la técnica de hematoxilina-eosina. Se determinó la concentración de proteínas totales por el método de Lowry y se realizaron corridas electroforéticas en gel de poliacrilamida SDS-PAGE al 12 por ciento para determinar el perfil proteico. Se realizó inmunomarcación para Bcl-2 con oro coloidal-plata y para p53 por streptavidina-biotina. Todos los animales tratados desarrollaron cambios similares a carcinomas a los 30 y 150 días. La concentracióan de proteínas totales aumentó significativamente (p<0,05) a los 7, 30 y 150 días en relación a los controles. En glándulas inducidas la inmunomarcación fue positiva para la proteína p53 en núcleos de células neoplásicas a los 30 y 150 días. En las mismas glándulas, la marcación citoplasmática de Bcl-2 fue positiva a los 7, 30 y 150 días(p=0,0015) y en relación a los controles (p<0,0001). No se observaron mutaciones de p53, mientras que se observó una mutación puntual, C A del gen bcl-2 a los 7, 30 y 150 días que generó un cambio de aminoácidos en la proteína (thre asn). Nuestros resultados sugieren que los cambios histopatológicos tempranos corresponden a modificaciones cuantitativas y cualitativas de las proteínas. Las modificaciones observadas a nivel histopatológico, bioquímico, inmunocitoquímico y genético en la carcinomgénesis experimental de glándula submandibular de rata podrían representar parámetros reproducibles de transformaciones malignas transferibles al ser humano, dada la alta homología de estos oncogenes entre rata, ratones...

Effects of soy oil on murine salivary tumorigenesis.

Dietary fat influences dimethylbenzanthracene (DMBA)-induced tumorigenesis of several organs, including the salivary glands. There is not enough evidence to suggest that soy oil could also affect growth of salivary tumors. The main purpose of this work therefore was to study the effects of dietary soy oil on macroscopic parameters of chemically induced murine salivary gland tumors. Eighty BALB/c male mice were assigned to four groups: soy oil (SO), corn oil (CO, control), fish oil (FO) and olein (O). Two weeks later, tumors were induced by 9,10-dimethyl-1,2-benzanthracene (DMBA). At the 13th post-injection week, the animals were sacrificed. In vivo tumor diameter, gland volume (total resected mass), tumor volume (microscopically measured), tumor remission and tumor histopathology were analyzed. The initial in vivo tumor diameter, gland and tumor volume were significantly greater in soy oil than in fish oil group. 26.7% of animals on the soy oil diet showed tumor remission. Sarcomas were more often found in the SO group, carcinomas in FO and the mixed-type tumors both in SO and CO groups. This study shows that the soy oil treatment resulted in larger tumors, some of which later became undetectable. It is necessary to further investigate these divergent results.

Skin and salivary gland carcinogenicity of 7,12-dimethylbenz[a]anthracene is equivalent in the presence or absence of aryl hydrocarbon receptor.

7,12-Dimethylbenz[a]anthracene (DMBA) is a well-known polycyclic aromatic hydrocarbon (PAH) that causes a variety of tumors in exposed animals. Although PAH carcinogenicity is primarily mediated by the aryl hydrocarbon receptor (AhR) through induction of P450, it is not precisely determined whether AhR regulates the DMBA carcinogenesis in vivo. In this context, we examined the frequency of DMBA-induced tumors and the expressions of mRNAs of P450-CYP1 subfamily and microsomal epoxide hydrolase (mEH) in the skin and submandibular gland using AhR-deficient mice. After DMBA exposure, AhR-/- and AhR+/+ mice showed the same tumor incidences and latency. CYP1A1 was absent in these tissues but was slightly induced in DMBA-treated AhR+/+ mice. In AhR-/- and AhR+/+ mice, constitutive expression of CYP1B1 was evident at equivalent levels, whereas CYP1A2 was not detectable, irrespective of DMBA treatment. mEH was expressed in both tissues of all animals. Collectively, the constitutive levels of CYP1B1 and mEH in the skin and submandibular gland maintain DMBA response in these tissues of AhR-/- mice.

Carcinogenic susceptibility to N-bis(2-hydroxypropyl)nitrosamine (DHPN) in rasH2 mice.

To evaluate the susceptibility of rasH2 mice to N-bis(2-hydroxypropyl)nitrosamine (DHPN), a potent carcinogen targeting the lung, liver, thyroid, and kidney, male, 6-week old, rasH2 mice and wild-type littermates (non-Tg mice) were given DHPN in drinking water at 0, 20 or 200 ppm, and 0 or 200 ppm, respectively, for 26 weeks. The experiment using rasH2 mice given 200 ppm DHPN and non-Tg mice given 200 and 0 ppm DHPN was completed at 20 weeks, since mortality in these groups was remarkably increased due to hemangiosarcomas of the liver. Histologically, tumors developed in the lung and liver in both rasH2 and non-Tg mice treated with DHPN. In addition, proliferative lesions were observed in the forestomach, urethra, and excretory duct of salivary glands in rasH2 mice given 200 ppm DHPN. RT-PCR analysis showed no marked difference in expression of mRNAs for the transgene and the endogenous mouse ras gene between the whole lung tissue containing a neoplasm and normal lung tissue. Our results suggest that rasH2 mice are highly susceptible to DHPN, the target organs including the forestomach, salivary gland and urethra, which have not been found to develop tumors in previous long-term carcinogenicity studies of DHPN in rats and mice.

[Proliferation and apoptosis in tongue epithelium of mice bearing salivary tumors induced by dimetilbenzantraceno (DMBA) and modulated by dietary lipids]. / Proliferación y apoptosis en epitelio lingual de ratones con tumores salivales inducidos por dimetilbenzantraceno (DMBA) y modulados por lípidos dietarios.

INTRODUCTION: According to the concept of field defects during the carcinogenesis process, excessive epithelial proliferation/apoptosis may exist in areas near tumors. Proliferation or apoptosis could be modified by dietary lipids. PURPOSE: The present study was designed to analyze proliferation and apoptosis in tongue epithelium of mice fed diets based on different lipids followed by induction of salivary tumors with DMBA. MATERIALS AND METHODS: Forty-five days after weaning, ten BALB/c mice were assigned to two diets: corn oil (CO) and fish oil (cod liver, FO). Two weeks later, DMBA was injected in the submandibular area. Animals were sacrificed at the 13th post-injection week. Samples of tongue were fixed in formalin-ethanol and immunohistochemically stained for proliferation (Ki-67) and apoptosis (Bax). By light microscopy, the number of nuclei positive for these markers were counted out of three-hundred total interphase cells both in dorsal and in ventral tongue surfaces. Results were analyzed through Analysis of Variance and t Test. RESULTS: Cell proliferation was greater in dorsal than in ventral tongue surfaces (p < 0.0001) with no diet difference. Apoptosis was significantly greater in mice fed FO than CO, particularly in tongue dorsal epithelia (p < 0.018). CONCLUSIONS: This study shows that FO diet induces higher levels of apoptosis in tongue epithelia suggesting a tissue defensive mechanism when exposed to a carcinogenic-tumoral agent.

Proliferación y apoptosis en epitelio lingual de ratones con tumores salivales inducidos por dimetilbenzantraceno (DMBA) y modulados por lípidos dietarios / Proliferation and apoptosis in tongue epithelium of mice bearing salivary tumors induced by dimetilbenzantraceno (DMBA) and modulated by dietary lipids

INTRODUCTION: According to the concept of field defects during the carcinogenesis process, excessive epithelial proliferation/apoptosis may exist in areas near tumors. Proliferation or apoptosis could be modified by dietary lipids. PURPOSE: The present study was designed to analyze proliferation and apoptosis in tongue epithelium of mice fed diets based on different lipids followed by induction of salivary tumors with DMBA. MATERIALS AND METHODS: Forty-five days after weaning, ten BALB/c mice were assigned to two diets: corn oil (CO) and fish oil (cod liver, FO). Two weeks later, DMBA was injected in the submandibular area. Animals were sacrificed at the 13th post-injection week. Samples of tongue were fixed in formalin-ethanol and immunohistochemically stained for proliferation (Ki-67) and apoptosis (Bax). By light microscopy, the number of nuclei positive for these markers were counted out of three-hundred total interphase cells both in dorsal and in ventral tongue surfaces. Results were analyzed through Analysis of Variance and t Test. RESULTS: Cell proliferation was greater in dorsal than in ventral tongue surfaces (p < 0.0001) with no diet difference. Apoptosis was significantly greater in mice fed FO than CO, particularly in tongue dorsal epithelia (p < 0.018). CONCLUSIONS: This study shows that FO diet induces higher levels of apoptosis in tongue epithelia suggesting a tissue defensive mechanism when exposed to a carcinogenic-tumoral agent.(AU)

Introducción: Según el concepto de cancerización de campo, existría alteración en la proliferación epitelial en áreas cercanas a tumores. Dicha proliferación podría ser modificada por lípidos dietarios. Objetivos: este estudio fue diseñado para analizar proliferación y apoptosis en epitelio lingual de ratones portadores de tumores salivalesinducidos por DMBA y alimentados con dietas a base de diferentes lípidos. Materiales y Métodos: Cuarenta y cinco días posteriores al destete, diez ratones BALB/c fueron asignados a dos dietas: maíz(M) y bacalao (B). Dos semanas después se inyectó DMBA en la zona submandibular. Los animales fueron sacrificados a ala 13º semana post-inyección. Muestras de lengua fueron fijadas en formal-etanl y procesadas inmunohistoquímicamente con marcadores de proliferación (Ki-67) y apoptosis. Mediante microscopia óptica, se efectuó un conteo de núcleos positivos a ambos marcadosres en un total de trecientas células en interfase, tanto en cara dorsal como ventral de lengua. Los resultados fueron analizados mediante Anális de Varianza y Test t. Resultados: La proliferación celular fue mayor en cara dorsal que en ventral (p> 0.001), sin diferencias por dieta. La apoptosis fue significativamentes mayor en ratones alimentados con B que M, en particular en cara dorsal (p<0.018). Conclusiones: Este estudio demuestra que la dieta B induce mayor apoptosis en ela epitelio lingua, sgiriendo un mecanismo defensivo de los tejidos ante el agente cancerígeno-tumoral. (AU)

Proliferación y apoptosis en epitelio lingual de ratones con tumores salivales inducidos por dimetilbenzantraceno (DMBA) y modulados por lípidos dietarios / Proliferation and apoptosis in tongue epithelium of mice bearing salivary tumors induced by dimetilbenzantraceno (DMBA) and modulated by dietary lipids

INTRODUCTION: According to the concept of field defects during the carcinogenesis process, excessive epithelial proliferation/apoptosis may exist in areas near tumors. Proliferation or apoptosis could be modified by dietary lipids. PURPOSE: The present study was designed to analyze proliferation and apoptosis in tongue epithelium of mice fed diets based on different lipids followed by induction of salivary tumors with DMBA. MATERIALS AND METHODS: Forty-five days after weaning, ten BALB/c mice were assigned to two diets: corn oil (CO) and fish oil (cod liver, FO). Two weeks later, DMBA was injected in the submandibular area. Animals were sacrificed at the 13th post-injection week. Samples of tongue were fixed in formalin-ethanol and immunohistochemically stained for proliferation (Ki-67) and apoptosis (Bax). By light microscopy, the number of nuclei positive for these markers were counted out of three-hundred total interphase cells both in dorsal and in ventral tongue surfaces. Results were analyzed through Analysis of Variance and t Test. RESULTS: Cell proliferation was greater in dorsal than in ventral tongue surfaces (p < 0.0001) with no diet difference. Apoptosis was significantly greater in mice fed FO than CO, particularly in tongue dorsal epithelia (p < 0.018). CONCLUSIONS: This study shows that FO diet induces higher levels of apoptosis in tongue epithelia suggesting a tissue defensive mechanism when exposed to a carcinogenic-tumoral agent.

Introducción: Según el concepto de cancerización de campo, existría alteración en la proliferación epitelial en áreas cercanas a tumores. Dicha proliferación podría ser modificada por lípidos dietarios. Objetivos: este estudio fue diseñado para analizar proliferación y apoptosis en epitelio lingual de ratones portadores de tumores salivalesinducidos por DMBA y alimentados con dietas a base de diferentes lípidos. Materiales y Métodos: Cuarenta y cinco días posteriores al destete, diez ratones BALB/c fueron asignados a dos dietas: maíz(M) y bacalao (B). Dos semanas después se inyectó DMBA en la zona submandibular. Los animales fueron sacrificados a ala 13º semana post-inyección. Muestras de lengua fueron fijadas en formal-etanl y procesadas inmunohistoquímicamente con marcadores de proliferación (Ki-67) y apoptosis. Mediante microscopia óptica, se efectuó un conteo de núcleos positivos a ambos marcadosres en un total de trecientas células en interfase, tanto en cara dorsal como ventral de lengua. Los resultados fueron analizados mediante Anális de Varianza y Test t. Resultados: La proliferación celular fue mayor en cara dorsal que en ventral (p> 0.001), sin diferencias por dieta. La apoptosis fue significativamentes mayor en ratones alimentados con B que M, en particular en cara dorsal (p<0.018). Conclusiones: Este estudio demuestra que la dieta B induce mayor apoptosis en ela epitelio lingua, sgiriendo un mecanismo defensivo de los tejidos ante el agente cancerígeno-tumoral.

Studies on the carcinogenicity of potassium iodide in F344 rats.

A chronic toxicity and carcinogenicity study, in which male and female F344/DuCrj rats were given potassium iodide (KI) in the drinking water at concentrations of 0, 10, 100 or 1000 ppm for 104 weeks, and a two-stage carcinogenicity study of application at 0 or 1000 ppm for 83 weeks following a single injection of N-bis(2-hydroxypropyl)nitrosamine (DHPN), were conducted. In the former, squamous cell carcinomas were induced in the salivary glands of the 1000 ppm group, but no tumors were observed in the thyroid. In the two-stage carcinogenicity study, thyroidal weights and the incidence of thyroid tumors derived from the follicular epithelium were significantly increased in the DHPN+KI as compared with the DHPN alone group. The results of our studies suggest that excess KI has a thyroid tumor-promoting effect, but KI per se does not induce thyroid tumors in rats. In the salivary gland, KI was suggested to have carcinogenic potential via an epigenetic mechanism, only active at a high dose.