The efficacy of chemotherapy re-challenge in third-line setting for metastatic colorectal cancer patients: a real-world study / 中华肿瘤杂志

Objective: To explore the efficacy of chemotherapy re-challenge in the third-line setting for patients with metastatic colorectal cancer (mCRC) in the real world. Methods: The clinicopathological data, treatment information, recent treatment efficacy, adverse events and survival data of mCRC patients who had disease progression after treatment with oxaliplatin-based and/or irinotecan-based chemotherapy and received third-line chemotherapy re-challenge from January 2013 to December 2020 at Tianjin Medical University Cancer Institute and Hospital were retrospectively collected. Survival curves were plotted with the Kaplan-Meier method, and the Cox proportional hazard model was used to analyze the prognostic factors. Results: A total of 95 mCRC patients were included. Among them, 32 patients (33.7%) received chemotherapy alone and 63 patients (66.3%) received chemotherapy combined with targeted drugs. Eighty-three patients were treated with dual-drug chemotherapy (87.4%), including oxaliplatin re-challenge in 35 patients and irinotecan re-challenge in 48 patients. The remaining 12 patients were treated with triplet chemotherapy regimens (12.6%). Among them, as 5 patients had sequential application of oxaliplatin and irinotecan in front-line treatments, their third-line therapy re-challenged both oxaliplatin and irinotecan; 7 patients only had oxaliplatin prescription before, and these patients re-challenged oxaliplatin in the third-line treatment. The overall response rate (ORR) and disease control rate (DCR) reached 8.6% (8/93) and 61.3% (57/93), respectively. The median progression free survival (mPFS) and median overall survival (mOS) were 4.9 months and 13.0 months, respectively. The most common adverse events were leukopenia (34.7%) and neutropenia (34.7%), followed by gastrointestinal adverse reactions such as nausea (32.6%) and vomiting (31.6%). Grade 3-4 adverse events were mostly hematological toxicity. Cox multivariate analysis showed that gender (HR=1.609, 95% CI: 1.016-2.548) and the PFS of front-line treatments (HR=0.598, 95% CI: 0.378-0.947) were independent prognostic factors. Conclusion: The results suggested that it is safe and effective for mCRC patients to choose third-line chemotherapy re-challenge, especially for patients with a PFS of more than one year in front-line treatments.

The efficacy of chemotherapy re-challenge in third-line setting for metastatic colorectal cancer patients: a real-world study / 中华肿瘤杂志

Objective: To explore the efficacy of chemotherapy re-challenge in the third-line setting for patients with metastatic colorectal cancer (mCRC) in the real world. Methods: The clinicopathological data, treatment information, recent treatment efficacy, adverse events and survival data of mCRC patients who had disease progression after treatment with oxaliplatin-based and/or irinotecan-based chemotherapy and received third-line chemotherapy re-challenge from January 2013 to December 2020 at Tianjin Medical University Cancer Institute and Hospital were retrospectively collected. Survival curves were plotted with the Kaplan-Meier method, and the Cox proportional hazard model was used to analyze the prognostic factors. Results: A total of 95 mCRC patients were included. Among them, 32 patients (33.7%) received chemotherapy alone and 63 patients (66.3%) received chemotherapy combined with targeted drugs. Eighty-three patients were treated with dual-drug chemotherapy (87.4%), including oxaliplatin re-challenge in 35 patients and irinotecan re-challenge in 48 patients. The remaining 12 patients were treated with triplet chemotherapy regimens (12.6%). Among them, as 5 patients had sequential application of oxaliplatin and irinotecan in front-line treatments, their third-line therapy re-challenged both oxaliplatin and irinotecan; 7 patients only had oxaliplatin prescription before, and these patients re-challenged oxaliplatin in the third-line treatment. The overall response rate (ORR) and disease control rate (DCR) reached 8.6% (8/93) and 61.3% (57/93), respectively. The median progression free survival (mPFS) and median overall survival (mOS) were 4.9 months and 13.0 months, respectively. The most common adverse events were leukopenia (34.7%) and neutropenia (34.7%), followed by gastrointestinal adverse reactions such as nausea (32.6%) and vomiting (31.6%). Grade 3-4 adverse events were mostly hematological toxicity. Cox multivariate analysis showed that gender (HR=1.609, 95% CI: 1.016-2.548) and the PFS of front-line treatments (HR=0.598, 95% CI: 0.378-0.947) were independent prognostic factors. Conclusion: The results suggested that it is safe and effective for mCRC patients to choose third-line chemotherapy re-challenge, especially for patients with a PFS of more than one year in front-line treatments.

Efecto del aceite de Sacha Inchi (Plukenetia volubilis L.) en la carcinogénesis de colon inducida por 1,2–dimetilhidrazina en ratas Holtzman / Effect of Sacha Inchi oil (Plukenetia volubilis L.) on 1,2–dimethylhydrazine-induced colon carcinogenesis in Holtzman rats

Objetivos: Evaluar el efecto protector del aceite de Sacha Inchi (ASI) sobre el desarrollo de cáncer de colon (CC) inducido con 1,2–dimetilhidrazina (DMH) en ratas Holtzman. Materiales y métodos: Estudio experimental con 28 ratas albinas machos de la cepa Holtzman distribuidas al azar en 4 grupos: un grupo control positivo expuesto a DMH (C1), un grupo control negativo expuesto a ASI a 150 μL/kg/día (C2), y dos grupos experimentales expuestos a DMH con ASI a 150 μL/kg/día (E1) y ASI a 300 μL/kg/día (E2). La DMH se aplicó por 8 semanas y con un tiempo total de inducción de 22 semanas. Luego se realizó el análisis patológico mediante la identificación de lesiones tumorales cancerosas en los intestinos. El efecto protector se evaluó en base a las proporciones de ausencia de lesión en los grupos expuestos a DMH. Resultados: Se identificaron lesiones tumorales cancerosas en: dos especímenes del grupo C1, un espécimen del grupo E1 y dos especímenes del grupo E2. No se identificaron lesiones intestinales en el grupo C2. Las proporciones de ausencia de lesión fueron: en el grupo C1 de 75%, en el grupo E1 de 87,5% y en el grupo E2 de 75%. No se encontraron diferencias significativas (p>0,05). Conclusiones: No se evidenció un efecto protector significativo del ASI sobre el desarrollo de CC inducido con DMH en ratas Holtzman, respecto al grupo control.

Objectives: To evaluate the preventive effect of Sacha Inchi oil (SIO) on 1,2–dimethylhydrazine (DMH)-induced colon carcinogenesis (CC) in Holtzman rats. Materials and methods: Experimental study with 28 Holtzman male albino rats randomly distributed into 4 groups: a positive control group exposed to DMH (C1), a negative control group exposed to SIO at 150 uL/kg/ day (C2), and two experimental groups exposed to DMH with SIO at 150 uL/kg/day (E1) and SIO at 300 uL/kg/day (E2). The DMH was applied for 8 weeks and the total induction time was 22 weeks. Pathological examination was performed by identifying cancerous tumor lesions in the guts. The preventive effect was evaluated based on proportions of lack of lesion in the groups exposed to DMH. Results: Cancerous tumor lesions were identified in: two specimens of group C1, one specimen of group E1 and two specimens of group E2. No intestinal lesions were identified in group C2. The proportions of lack of lesion were: in group C1 of 75%, in group E1 of 87.5% and group E2 of 75%. No significant differences were found (p>0.05). Conclusions: It was not found a significant protective effect of SIO on DMH-induced CC in Holtzman rats, compared to control group.

Secondary bile acids effects in colon pathology. Experimental mice study

ABSTRACTPURPOSE:To assess whether deoxycholic acid (DOC) and lithocholic acid (LCA) administered in a period of six months in a concentration of 0.25% may have a carcinogenic role in mice colon.METHODS:The study used C57BL6 female mice divided into four groups. The control group received a balanced diet and the others received diets supplemented with 0.25% DOC, 0.25% LCA and 0.125% DOC+0.125% LCA, respectively. After euthanasia, the lesions found in the resected gastrointestinal tracts were stained with hematoxylin-eosin and examined microscopically.RESULTS:No gastrointestinal tract changes were observed in the control group, while hyperplastic Peyer's patches in the small intestine, flat adenomas with mild dysplasia and chronic colitis at the level of the colon were found in all three test groups. The colonic lesions prevailed in the proximal colon. The highest number of flat adenoma lesions (8), hyperplasia of Peyer's patches (25) and chronic colitis (2) were found in mice fed with diet and LCA.CONCLUSION: Precancerous or cancerous pathological lesions could not be identified. Instead, adenomatous colonic injuries occurred in a shorter period of time (six months), compared to the reported data.

Efectos in vitro e in vivo de la pulpa de mango (Mangifera indica cv. Azúcar) en la carcinogénesis de colon / In vitro and in vivo effects of mango pulp (Mangifera indica cv. Azucar) in colon carcinogenesis.

La porción comestible del mango contiene ácido ascórbico, carotenoides, polifenoles, terpenoides y fibra que tienen efectos protectores para la salud, y posiblemente contra el desarrollo de cáncer de colon (CCO). El objetivo de este estudio fue evaluar la capacidad antiproliferativa en células de adenocarcinoma de colon (SW480) y preventiva en un modelo in vivo de CCO de un extracto acuoso de Mangifera indica cv. Azúcar. El contenido de fenoles totales, flavonoides y carotenoides también fue analizado. El extracto inhibió el crecimiento de las células SW480 en forma dosistiempo- dependiente hasta 22,3% luego de 72h de exposición al extracto (200 μg/mL). La carcinogénesis en el colon de ratones Balb/c fue inducida mediante dos inyecciones intraperitoneales de azoximetano (AOM) a la tercera y cuarta semana de haber iniciado el suministro de mango en el líquido de bebida (0,3%, 0,6%, 1,25%). Después de 10 semanas de tratamiento se observó inhibición dosis-dependiente de la formación de focos de criptas aberrantes (FCA); 0,3% de mango inhibió más del 60% de FCA (p=0,05) comparado con los controles que recibieron agua. Estos resultados muestran que la pulpa del mango de azúcar, un alimento natural, no tóxico, que forma parte de la dieta del ser humano contiene compuestos bioactivos capaces de reducir el crecimiento de células tumorales y prevenir la aparición de las lesiones precancerosas en colon durante el inicio de la carcinogénesis.

Mango pulp contains ascorbic acid, carotenoids, polyphenols, terpenoids and fiber which are healthy and could protect against colon cancer. The aim of this study was to evaluate the antiproliferative and preventive capacity of an aqueous extract of Mangifera indica cv. Azúcar on a human colon adenocarcinoma cell line (SW480) and in a rodent model of colorectal cancer, respectively. The content of total phenolics, flavonoids and carotenoids were also analyzed in the extract. SW480 cell growth was inhibited in a dose and time dependent manner by 22.3% after a 72h exposure to the extract (200 μg/ mL). Colon carcinogenesis was initiated in Balb/c mice by two intra-peritoneal injections of azoxymethane (AOM) at the third and fourth week of giving mango in drinking water (0.3%, 0.6%, 1.25%). After 10 weeks of treatment, in the colon of mice receiving 0.3% mango, aberrant crypt foci formation was inhibited more than 60% (p=0,05) and the inhibition was dose-dependent when compared with controls receiving water. These results show that mango pulp, a natural food, non toxic, part of human being diet, contains bioactive compounds able to reduce growth of tumor cells and to prevent the appearance of precancerous lesions in colon during carcinogenesis initiation.

Ponderal behavior of rats fed an omegas 3, 6 and 9 enriched diet submitted to colon carcinogenesis induced by azoxymethane

PURPOSE: To assess weight changes in rats fed diets with different ratios of omegas 3, 6 and 9 submitted to colonic carcinogenesis induced by Azoxymethane (AOM). METHODS: Sixty rats with three weeks of life were distributed into five groups of specific diets containing 12 animals each: GI- Standard diet without adminstration of AOM, GII- Standard diet with adminstration of AOM; GIII- Hyperlipidic diet with adminstration of AOM; GIV-Normolipidic diet with adminstration of AOM; GV- Hypolipidic diet with adminstration of AOM. The weight and food intake of each group were assessed four times in each week throughout the experiment until euthanasia at 36th week. RESULTS: GI and GII had no significant difference in weight. GI showed a significant increase when compared to GIII, GIV and GV. GII also showed a significant increase when compared to GIII, GIV and GV. When comparing intake of GI as compared to GII no significant difference was found, however such groups had higher intake than groups III, IV and V. There were found no difference in weight when comparing amoung rats with and without cancer within each groups: GII, GIII, GIV and GV. CONCLUSIONS: Diets rich in omega 3, 6 and 9 reduced food intake and weight. Rats with colorectal cancer had no decrease in weight as compared to those without this condition in the same group.

Use of defatted flaxseed meal reduces precancerous colon lesions in C57BL/6 mice

PURPOSE: To investigate the hemopreventive effect of defatted flaxseed meal in C57BL/6 mice after induction of precancerous colon lesions with 1.2-dimethylhydrazine (DMH). METHODS: Thirty-six 12-week-old C57BL/6 mice were divided into three treatment groups(n=12 in each group): (1) diet with 10% defatted flaxseed meal; (2) diet with defatted flaxseed meal and precancerous colon lesions induced by DMH; and (3) precancerous colon lesions induced by DMH, without defatted flaxseed meal. The incidence of aberrant crypt foci (ACF), oxidative processes, expression of tumor suppressor proteins and cyclins, as well as the profile of short-chain fatty acids (SCFA) in animal feces were investigated in the presence and absence of DMH. RESULTS: The rats consuming defatted flaxseed meals showed lesions with lower multiplicity and a reduced incidence of lesions. No changes in the expression of tumor suppressor proteins and those involved in cell cycle control were detected. CONCLUSION: Defatted flaxseed meal protected the distal colon of mice from precancerous lesions.

Effect of probiotics on the development of dimethylhydrazine-induced preneoplastic lesions in the mice colon

PURPOSE: To determine the effect of probiotics on the development of chemically induced (1, 2-dimethylhydrazine) colonic preneoplastic lesions, in mice. METHODS: The animals were divided into five groups. The control group was injected with carcinogen alone and the other groups also received probiotics (1- Lactobacillus delbrueckii UFV-H2b20; 2- Bifidobacterium animalis var. lactis Bb12; 3- L. delbrueckii UFV-H2b20 plus B. animalis var. lactis Bb12; and 4- Saccharomyces boulardii) administered orally in drinking water throughout fourteen weeks. RESULTS: Consumption of lactobacilli and bifidobacteria alone resulted in a significant reduction of the total number of aberrant crypt foci (55.7% and 45.1%, respectively). Significant reduction in the number of these small foci (<3 aberrant crypts) was only observed in the group treated with lactobacilli (52.2%) in comparison to control group. The number of larger foci (>3 aberrant crypts) crypts had no significant reduction. CONCLUSION: L. delbrueckii UFV-H2b20 and B. animalis var. lactis Bb12 administered alone protect colonic preneoplastic lesions in mice, while the combined treatment of these bacteria and the administration of S.boulardii were not effective in reducing such colonic lesions.

Chemopreventive and metabolic effects of inulin on colon cancer development

Prebiotics modulate microbial composition and ensure a healthy gastrointestinal tract environment that can prevent colon cancer development. These natural dietary compounds are therefore potential chemopreventive agents. Thirty Sprague-Dawley rats (4 months old) were experimentally treated with procarcinogen dimethylhydrazine to induce colon cancer development. The rats were randomly assigned to three groups: a control group (CG), a group treated with dimethylhydrazine (DMH), and a group given DMH and inulin, a prebiotic (DMH+PRE). The effects of inulin on the activities of bacterial glycolytic enzymes, short-chain fatty acids, coliform and lactobacilli counts, cytokine levels, and cyclooxygenase-2 (COX-2) and transcription nuclear factor kappa beta (NFkappaB) immunoreactivity were measured. Inulin significantly decreased coliform counts (p < 0.01), increased lactobacilli counts (p < 0.001), and decreased the activity of beta-glucuronidase (p < 0.01). Butyric and propionic concentrations were decreased in the DMH group. Inulin increased its concentration that had been reduced by DMH. Inulin decreased the numbers of COX-2- and NFkappaB-positive cells in the tunica mucosae and tela submucosae of the colon. The expression of IL-2, TNFalpha, and IL-10 was also diminished. This 28-week study showed that dietary intake of inulin prevents preneoplastic changes and inflammation that promote colon cancer development.

Efficacy of geraniol but not of β-ionone or their combination for the chemoprevention of rat colon carcinogenesis

β-ionone (βI), a cyclic isoprenoid, and geraniol (GO), an acyclic monoterpene, represent a promising class of dietary chemopreventive agents against cancer, whose combination could result in synergistic anticarcinogenic effects. The chemopreventive activities of βI and GO were evaluated individually or in combination during colon carcinogenesis induced by dimethylhydrazine in 48 3-week-old male Wistar rats (12 per group) weighing 40-50 g. Animals were treated for 9 consecutive weeks with βI (16 mg/100 g body weight), GO (25 mg/100 g body weight), βI combined with GO or corn oil (control). Number of total aberrant crypt foci (ACF) and of ACF ≥4 crypts in the distal colon was significantly lower in the GO group (66 ± 13 and 9 ± 2, respectively) compared to control (102 ± 9 and 17 ± 3) and without differences in the βI (91 ± 11 and 14 ± 3) and βI+GO groups (96 ± 5 and 19 ± 2). Apoptosis level, identified by classical apoptosis morphological criteria, in the distal colon was significantly higher in the GO group (1.64 ± 0.06 apoptotic cells/mm²) compared to control (0.91 ± 0.07 apoptotic cells/mm²). The GO group presented a 0.7-fold reduction in Bcl-2 protein expression (Western blot) compared to control. Colonic mucosa concentrations of βI and GO (gas chromatography/mass spectrometry) were higher in the βI and GO groups, respectively, compared to the control and βI+GO groups. Therefore, GO, but not βI, represents a potential chemopreventive agent in colon carcrvpdate=20110329inogenesis. Surprisingly, the combination of isoprenoids does not represent an efficient chemopreventive strategy.

Fish oil ingestion reduces the number of aberrant crypt foci and adenoma in 1, 2-dimethylhydrazine-induced colon cancer in rats

We determined the effect of fish oil (FO) ingestion on colonic carcinogenesis in rats. Male Wistar rats received 4 subcutaneous injections (40 mg/kg body weight each) of 1,2-dimethylhydrazine (DMH) at 3-day intervals and were fed a diet containing 18 percent by weight FO (N = 10) or soybean oil (SO, N = 10) for 36 weeks. At sacrifice, the colon was removed, aberrant crypt foci were counted and the fatty acid profile was determined. Intestinal tumors were removed and classified as adenoma or carcinoma. Liver and feces were collected and analyzed for fatty acid profile. FO reduced the mean (± SEM) number of aberrant crypt foci compared to SO (113.55 ± 6.97 vs 214.60 ± 18.61; P < 0.05) and the incidence of adenoma (FO: 20 percent vs SO: 100 percent), but carcinoma occurred equally in FO and SO rats (2 animals per group). The polyunsaturated fatty acid (PUFA) profile of the colon was affected by diet (P < 0.05): total ù-3 (FO: 8.18 ± 0.97 vs SO: 1.71 ± 0.54 percent) and total ù-6 (FO: 3.83 ± 0.59 vs SO: 10.43 ± 1.28 percent). The same occurred in the liver (P < 0.05): total ù-3 (FO: 34.41 ± 2.6 vs SO: 6.46 ± 0.59 percent) and total ù-6 (FO: 8.73 ± 1.37 vs SO: 42.12 ± 2.33 percent). The PUFA profile of the feces and liver polyamine levels did not differ between groups (P > 0.05). In conclusion, our findings indicate that chronic FO ingestion protected against the DMH-induced preneoplastic colon lesions and adenoma development, but not against carcinoma in rats.

Triptolide downregulates Rac1 and the JAK/STAT3 pathway and inhibits colitis-related colon cancer progression

Triptolide, a diterpenoid triepoxide from the traditional Chinese medicinal herb Tripterygium wilfordii Hook. f., is a potential treatment for autoimmune diseases as well a possible anti-tumor agent. It inhibits proliferation of coloretal cancer cells in vitro and in vivo. In this study, its ability to block progress of colitis to colon cancer, and its molecular mechanism of action are investigated. A mouse model for colitis-induced colorectal cancer was used to test the effect of triptolide on cancer progression. Treatment of mice with triptolide decreased the incidence of colon cancer formation, and increased survival rate. Moreover, triptolide decreased the incidence of tumors in nude mice inoculated with cultured colon cancer cells dose-dependently. In vitro, triptolide inhibited the proliferation, migration and colony formation of colon cancer cells. Secretion of IL6 and levels of JAK1, IL6R and phosphorylated STAT3 were all reduced by triptolide treatment. Triptolide prohibited Rac1 activity and blocked cyclin D1 and CDK4 expression, leading to G1 arrest. Triptolide interrupted the IL6R-JAK/STAT pathway that is crucial for cell proliferation, survival, and inflammation. This suggests that triptolide might be a candidate for prevention of colitis induced colon cancer because it reduces inflammation and prevents tumor formation and development.

Long-term aerobic swimming training by rats reduces the number of aberrant crypt foci in 1, 2-dimethylhydrazine-induced colon cancer

We determined the effect of long-term aerobic swimming training regimens of different intensities on colonic carcinogenesis in rats. Male Wistar rats (11 weeks old) were given 4 subcutaneous injections (40 mg/kg body weight each) of 1,2-dimethyl-hydrazine (DMH, dissolved in 0.9 percent NaCl containing 1.5 percent EDTA, pH 6.5), at 3-day intervals and divided into three exercise groups that swam with 0 percent body weight (EG1, N = 11), 2 percent body weight (EG2, N = 11), and 4 percent body weight of load (EG3, N = 10), 20 min/day, 5 days/week for 35 weeks, and one sedentary control group (CG, N = 10). At sacrifice, the colon was removed and counted for tumors and aberrant crypt foci. Tumor size was measured and intra-abdominal fat was weighed. The mean number of aberrant crypt foci was reduced only for EG2 compared to CG (26.21 ± 2.99 vs 36.40 ± 1.53 crypts; P < 0.05). Tumor incidence was not significantly different among groups (CG: 90 percent; EG1: 72.7 percent; EG2: 90 percent; EG3: 80 percent). Swimming training did not affect either tumor multiplicity (CG: 2.30 ± 0.58; EG1: 2.09 ± 0.44; EG2: 1.27 ± 0.19; EG3: 1.50 ± 0.48 tumors) or size (CG: 1.78 ± 0.24; EG1: 1.81 ± 0.14; EG2: 1.55 ± 0.21; EG3: 2.17 ± 0.22 cm³). Intra-abdominal fat was not significantly different among groups (CG: 10.54 ± 2.73; EG1: 6.12 ± 1.15; EG2: 7.85 ± 1.24; EG3: 5.11 ± 0.74 g). Aerobic swimming training with 2 percent body weight of load protected against the DMH-induced preneoplastic colon lesions, but not against tumor development in the rat.

Apoptotic effects of inositol hexaphosphate on biomarker Itpr3 in induced colon rat carcinogenesis

PURPOSE: To study the effect of the modulation of inositol hexaphosphate (IP6) in the biological immunohistochemistry expression of cellular signaling marker apoptosis, in model of carcinogenesis of colon induced by azoxymethane (AOM). METHODS: Wistar rats (N=112) distributed in 4 groups (n=28): Control; B, AOM (5 mg kg-1, 2x, to break week 3); C, IP6 (in water 1 percent, six weeks); D, IP6+AOM. Weekly euthanasia (n=7), from week three. Immunohistochemistry of ascendant colon with biological marker inositol 1,4,5 triphosphate receptor type III (Itpr3). Quantification of the immune-expression with use of computer-assisted image processing. Analysis statistics of the means between groups, weeks in groups, groups in weeks, and established significance when p<0.05. RESULTS: One proved significant difference between groups in the expression of Itpr3, p<0.0001; with Itpr3 reduction of BxD group, p<0.001. CONCLUSION: Inositol hexaphosphate promotes modulation of biological markers with reduction of Itpr3 in carcinogenesis of colon.

OBJETIVO: Estudar os efeitos da modulação do inositol hexafosfato (IP6) na expressão imunoistoquímica de marcador biológico de sinalização celular de apoptose, em modelo de carcinogênese induzida pelo azoximetano (AOM). MÉTODOS: Ratos Wistar (N=112) distribuídos em 4 grupos (n=28): A, controle; B, AOM (5 mg Kg-1, 2x, a partir semana 3); C, IP6 (em água a 1 por cento, seis semanas); D, IP6+AOM. Eutanásia semanal (n=7), a partir de semana três. Imunoistoquímica de colo ascendente com marcador biológico inositol 1,4,5 trisphosphate receptor type III (Itpr3). Quantificação da imunoexpressão com uso de processamento imagem assistida computador. Análise estatística da expressão média entre grupos, semanas em grupos e grupos em semanas, e estabelecido significância quando p<0.05. RESULTADOS: Evidenciou-se diferença significante entre grupos na expressão de Itpr3, p<0.0001; com diminuição Itpr3 de grupo BxD, p<0.001. CONCLUSÃO: O inositol hexafostato promove a modulação de marcador biológico com diminuição Itpr3 em carcinogênese de colo.

Intrinsic denervation of the colon is associated with a decrease of some colonic preneoplastic markers in rats treated with a chemical carcinogen

Denervation of the colon is protective against the colon cancer; however, the mechanisms involved are unknown. We tested the hypothesis that the denervated colonic mucosa could be less responsive to the action of the chemical carcinogen dimethylhydrazine (DMH). Three groups of 32 male Wistar rats were treated as follows: group 1 (G1) had the colon denervated with 0.3 mL 1.5 mM benzyldimethyltetradecylammonium (benzalkonium chloride, BAC); G2 received a single ip injection of 125 mg/kg DMH; G3 was treated with BAC + the same dose and route of DMH. A control group (Sham, N = 32) did not receive any treatment. Each group was subdivided into four groups according to the sacrifice time (1, 2, 6, and 12 weeks after DMH). Crypt fission index, ß-catenin accumulated crypts, aberrant crypt foci, and cell proliferation were evaluated and analyzed by ANOVA and the Student t-test. G3 animals presented a small number of aberrant crypt foci and low crypt fission index compared to G2 animals after 2 and 12 weeks, respectively. From the second week on, the index of ß-catenin crypt in G3 animals increased slower than in G2 animals. From the 12th week on, G2 animals presented a significant increase in cell proliferation when compared to the other groups. Colonic denervation plays an anticarcinogenic role from early stages of colon cancer development. This finding can be of importance for the study of the role of the enteric nervous system in the carcinogenic process.

Inhibition of lipid peroxidation and enhancement of GST activity by cardamom and cinnamon during chemically induced colon carcinogenesis in Swiss albino mice.

Globally, colorectal cancer is the third commonest cancer in men since 1975.The present study focuses on the preventive strategies aimed at reducing the incidences and mortality of large bowel cancer. Chemoprevention of colon cancer appears to be a very realistic possibility because various intermediate stages have been identified preceding the development of malignant colonic tumors. Several studies have demonstrated that generous consumption of vegetables reduces the risk of colon cancer. This idea has prompted the present investigation to search for some novel plant products, which may have possible anticarcinogenic activity. It has already been proved from various experiments that chemopreventive agents, by virtue of their anti-oxidant, anti-inflammatory, anti-proliferative, apoptosis-inducing activity, act at various levels including molecular, cellular, tissue and organ levels to interfere with carcinogens. Previous studies from our laboratory have already reported the inhibitory effect of cinnamon and cardamom on azoxymethane induced colon carcinogenesis by virtue of their anti-inflammatory, anti-proliferative and pro-apoptotic activity. This particular experiment was carried out to assess the anti-oxidative potential of these spices. Aqueous suspensions of cinnamon and cardamom have been shown to enhance the level of detoxifying enzyme (GST activity) with simultaneous decrease in lipid peroxidation levels in the treatment groups when compared to that of the carcinogen control group.

Preventive effects of a flavonoid myricitrin on the formation of azoxymethane-induced premalignant lesions in colons of rats.

The preventive effect of dietary exposure to a flavonoid myricitrin of azoxymethane (AOM)-induced aberrant crypt foci (ACF) and beta-catenin-accumulated crypts (BCAC) formation was investigated in male F344 rats. Thirty-four rats were divided randomly into five experimental groups. Rats in groups 1-3 were given subcutaneous injections of AOM (15 mg/kg body weight) once a week for 3 weeks. Starting 1 week before the first injection of AOM, rats in groups 2 and 3 were fed a diet containing 500 or 1000 ppm myricitrin, respectively, for 11 weeks. Rats in group 4 were fed a diet containing 1000 ppm myricitrin. Rats in groups 1 and 5 were given the basal diet alone during the study. The experiment was terminated 11 weeks after the start. The frequency of ACF per colon in group 3 treated with AOM and 1000 ppm myricitrin was significantly lower than that in group 1 treated with AOM alone (p<0.01). Furthermore, dietary myricitrin at both doses (groups 2 and 3) significantly inhibited the formation of BCAC when compared to group 1 (p<0.05). These results indicate that myricitrin had possible chemopreventive effects in the present short-term colon carcinogenesis bioassays and suggest that longer exposure may cause suppression of tumor development.

Effect of 2-(carboxyphenyl) retinamide and genistein on the formation of early lesions in 1,2-dimethylhydrazine-induced colon carcinogenesis in rats.

Aberrant crypt foci (ACF) are recognized as preneoplastic lesions for colon cancer, and ACF in rodents are widely used as an intermediate biomarker to predict tumorigenicity in the colon. However, a lack of correlations between the formation of ACF and the development of colonic tumors has been reported in several studies. For example, 2-(carboxyphenyl) retinamide (2-CPR) and genistein were reported to inhibit the carcinogen-induced formation of ACF, whereas both of them were later found to enhance colon tumorigenesis in rats treated with azoxymethane (AOM). Recently, we have identified b-catenin-accumulated crypts (BCAC) in the colon of rats shortly after administration of AOM, and provided evidence that these are independent early lesions of classical ACF, and BCAC might be direct precursors for colon cancers. In the present study, we performed a comparative analysis of the modifying effects of 2-CPR and genistein on 1,2-dimethylhydrazine (DMH)-induced BCAC and ACF in male F344 rats. Dietary administration of 2-CPR (315 ppm) significantly reduced the total number, multiplicity and size of ACF in DMH-exposed colonic mucosa, while genistein (250 ppm) had no significant effects on DMH-induced ACF formation. In contrast, both of 2-CPR and genistein significantly enhanced the multiplicity and size of DMH-induced BCAC when compared with DMH alone group. In addition, both 2-CPR and genistein significantly increased the proliferating cell nuclear antigen (PCNA) index preferentially in BCAC. Together with previous findings that 2-CPR and genistein are tumor promoters in the colon, our results support the concept that BCAC are precursors of colon tumors and suggest that these lesions are more reliable short-term biomarkers for colon carcinogenesis in rodents than ACF.

Antioxidative and modifying effects of a tropical plant Azadirachta indica (Neem) on azoxymethane-induced preneoplastic lesions in the rat colon.

The purpose of the present study was to examine whether Neem leaf (Azadirachta indica) has short-term chemopreventive effects on endpoint preneoplastic lesions involved in rat colon carcinogenesis and might also exert antioxidative activity. Forty- two male F344 rats were randomly divided into 6 experimental groups. Groups 1 to 4 were given a subcutaneous injection of azoxymethane (AOM, 20 mg/kg body weight) once a week for 2 weeks. Starting one week before the first injection of AOM, rats in groups 2 to 4 received an aqueous extract of Neem leaf (20, 100, and 250 mg/kg, respectively) by gavage 3 times per week, for 5 weeks. Rats in group 5 also were given the Neem extract by gavage feeding 3 times per week for 5 weeks, while group 6 served as untreated controls. The experiment was terminated 5 weeks after the start. Dietary feeding of the Neem extract at all dose levels significantly inhibited the induction of aberrant crypt foci (ACF) (P<0.0002), when compared to the AOM-treated group (group 1). In groups 2 to 4, treatment of rats with the Neem extract also significantly decreased the proliferating cell nuclear antigen (PCNA) labeling indices (P<0.0006) of colon epithelium and ACF. Moreover, the Neem extract also showed antioxidative activity. The finding that dietary Neem has possible chemopreventive effects in the present short-term colon carcinogenesis bioassay suggests that longer-term exposure may cause suppression of tumor development.