Protective effect of linoleic acid on liver toxicity induced by methotrexate / Efecto protector del ácido linoleico sobre la toxicidad hepática inducida por metotrexato

SUMMARY: We aimed to investigate the protective effect of linoleic acid on liver toxicity induced by methotrexate. The study was carried out in partnership with the Department of Anatomy and Department of Medical Pharmacology of Çukurova University Faculty of Medicine, using the laboratory facilities of the Department of Medical Pharmacology. Human hepatocyte cell line (CRL- 11233) cells obtained from the American Type Culture Collection Organization (ATCC) were used. Expressions of apoptotic pathway markers, apoptosis inducing factor (AIF), BAX, BCL 2, GADD 153, 78-kDa glucose-regulated protein (GRP78), and CASPASE-3 were evaluated. All analyzes were examined in four groups (Group 1; control, Group 2; linoleic acid given, Group 3; methotrexate given and Group 4; linoleic acid and methotrexate given). The mean ± standard error values of the obtained results as nanogram / milliliter (ng / ml) are in Group I, Group II, Group III and Group IV, respectively; AIF values, 0.4150 ± 0.1208, 0.3633 ± 0.2389, 1.792 ± 0.3611 and 1.077 ± 0.1646, BAX values, 0.900 ± 0.1864, 1.002 ± 0.2098, 8.352 ± 1.467 and 4.295 ± 1.522, BCL 2 values, 13.93 ± 1.198, 13.92 ± 1.739, 2.938 ± 1.059 and 9.250 ± 1.492, GADD 153, 0.7333 ± 0.1751, 0.7067 ± 0.2115, 1.650 ± 0.2950 and 1.237 ± 0.1805, GRP78, 0.4767 ± 0.1804, 0.5233 ± 0.1590, 2.183 ± 0.2639 and 1.112 ± 0.2693, CASPASE-3 values , 1.127 ± 0.2033, 0.8317 ± 0.3392, 13.50 ± 1.871 and 8.183 ± 1.030. It was determined that linoleic acid has a protective effect on methotrexate-induced liver toxicity.

Nuestro objetivo fue investigar el efecto protector del ácido linoleico sobre la toxicidad hepática inducida por metotrexato. El estudio se llevó a cabo en colaboración con el Departamento de Anatomía y el Departamento de Farmacología Médica de la Facultad de Medicina de la Universidad de Çukurova, utilizando las instalaciones del laboratorio del Departamento de Farmacología Médica. Se usaron células de la línea celular de hepatocitos humanos (CRL-11233) obtenidas de la American Type Culture Collection Organisation (ATCC). Se evaluaron las expresiones de marcadores de vías apoptóticas, factor inductor de apoptosis (AIF), BAX, BCL 2, GADD 153, proteína regulada por glucosa de 78 kDa (GRP78) y CASPASE-3. Todos los análisis se examinaron en cuatro grupos (Grupo 1; control, Grupo 2; se administró ácido linoleico, Grupo 3; se administró metotrexato y Grupo 4; se administró ácido linoleico y metotrexato). Los valores medios ± error estándar de los resultados obtenidos como nanogramo/mililitro (ng/ml) se encuentran en el Grupo I, Grupo II, Grupo III y Grupo IV, respectivamente; Valores de AIF, 0,4150 ± 0,1208, 0,3633 ± 0,2389, 1,792 ± 0,3611 y 1,077 ± 0,1646, valores de Bax, 0,900 ± 0,1864, 1,002 ± 0,2098, 8,352 ± 1,467 y 4,295 ± 1,522, BCL 2 valores, 13,93 ± 1,199. 2,938 ± 1,059 y 9,250 ± 1,492, GADD 153, 0,7333 ± 0,1751, 0,7067 ± 0,2115, 1,650 ± 0,2950 y 1,237 ± 0,1805, Grp78, 0,4767 ± 0,1804, 0,5233 ± 0,1590, 2,183, ± 1,263. 1,127 ± 0,2033, 0,8317 ± 0,3392, 13,50 ± 1,871 y 8,183 ± 1,030. Se determinó que el ácido linoleico tiene un efecto protector sobre la toxicidad hepática inducida por metotrexato.

Does alfa lipoic acid prevent liver from methotrexate induced oxidative injury in rats?

PURPOSE: To determine the antioxidant and anti-inflammatory effects of alfa lipoic acid (ALA) on the liver injury induced by methotrexate (MTX) in rats. METHODS: Thirty two rats were randomly assigned into four equal groups; control, ALA, MTX and MTX with ALA groups. Liver injury was performed with a single dose of MTX (20 mg/kg) to groups 3 and 4. The ALA was administered intraperitonealy for five days in groups 2 and 4. The other rats received saline injection. At the sixth day the rats decapitated, blood and liver tissue samples were removed for TNF-α, IL-1β, malondialdehyde, glutathione, myeloperoxidase and sodium potassium-adenosine triphosphatase levels measurement and histological examination. RESULTS: MTX administration caused a significant decrease in tissue GSH, and tissue Na+, K+ ATPase activity and which was accompanied with significant increases in tissue MDA and MPO activity. Moreover the pro-inflammatory cytokines (TNF-α, IL- β) were significantly increased in the MTX group. On the other hand, ALA treatment reversed all these biochemical indices as well as histopathological alterations induced by MTX. CONCLUSION: Alfa lipoic acid ameliorates methotrexate induced oxidative damage of liver in rats with its anti-inflammatory and antioxidant effects. .

Methotrexate-induced intestinal mucositis delays gastric emptying and gastrointestinal transit of liquids in awake rats / Mucosite induzida pelo metotrexato retarda o esvaziamento gástrico e o trânsito gastrointestinal de líquidos em ratos acordados

CONTEXT: Methotrexate and other anticancer agents can induce intestinal mucositis, which is one of the most common limiting factor that prevent further dose escalation of the methotrexate. OBJECTIVES: To evaluate the gastric emptying and gastrointestinal transit of liquids in methotrexate-induced intestinal mucositis. METHODS: Wistar rats received methotrexate (2.5 mg/kg/day for 3 days, subcutaneously) or saline. After 1, 3 and 7 days, sections of duodenum, jejunum and ileum were removed for assessment of epithelial damage and myeloperoxidase activity (biochemical marker of granulocyte infiltration). Others rats were pre-treated with methotrexate or saline, gavage-fed after 3 or 7 days with a standard test liquid meal, and sacrificed 10, 20 or 30-min later. Gastric and small intestine dye recoveries were measured by spectrophotometry. RESULTS: After 3 days of methotrexate, there was an epithelial intestinal damage in all segments, with myeloperoxidase activity increase in both in duodenum and ileum. Seven days after methotrexate, we observed a complete reversion of this intestinal damage. There was an increase in gastric dye recoveries after 10, 20, and 30-min post-prandial intervals after 3 days, but not after 7 days, of methotrexate. Intestine dye recoveries were decreased in the first and second segments at 10 min, in the third at 20 min, and in the second and third at 30 min, only after 3 days of methotrexate treatment. CONCLUSION: Methotrexate-induced intestinal mucositis delays gastric emptying and gastrointestinal transit of liquids in awake rats.

CONTEXTO: Metotrexato e outros agentes anticâncer podem induzir uma mucosite intestinal, que é um dos fatores de limitante mais comum que limitam o aumento escalonado da dose do metotrexato. OBJETIVOS: Avaliar o esvaziamento gástrico e o trânsito gastrointestinal de líquidos na mucosite intestinal induzida por metotrexato. MÉTODOS: Ratos Wistar, receberam metotrexato (2.5 mg/kg/dia por 3 dias, subcutâneo) ou salina. Após 1, 3 ou 7 dias, secções do duodeno, jejuno e íleo foram retirados para análise morfométrica e dosagem da atividade de mieloperoxidase (marcador bioquímico da infiltração de neutrófilos). Outros ratos foram pré-tratados com metotrexato ou salina, após 3 ou 7 dias, foram alimentados mediante gavagem com uma refeição teste e sacrificados após 10, 20 e 30 minutos. As retenções fracionais do corante no estômago e em três segmentos do intestino delgado foram determinados por espectrofotometria. RESULTADOS: Após 3 dias do metotrexato, houve lesão do epitélio intestinal em todos os segmentos, com aumento da atividade de mieloperoxidase, no duodeno e íleo. Sete dias após o metotrexato, foi observada completa reversão da lesão intestinal. Observou-se ainda retardo no esvaziamento gástrico após 10 min, 20 min e 30 min, após 3 dias, mas não após 7 dias do tratamento com metotrexato. A retenção fracional dos segmentos do intestino foi reduzida no primeiro e segundo segmentos após 10 min, e no terceiro segmento após 30 min da administração da refeição, somente 3 dias após o tratamento com metotrexato. CONCLUSÃO: A mucosite intestinal induzida por metotrexato retarda o esvaziamento gástrico e o trânsito gastrointestinal de líquidos em ratos acordados.

Avaliação da qualidade de vida e toxicidades em pacientes com câncer colorretal tratados com quimioterapia adjuvante baseada em fluoropirimidinas / Evaluation of the toxicity and quality of life in patients with colorectal cancer treated with chemotherapy

RACIONAL: O câncer colorretal é a quarta causa de câncer no Brasil e o 5-fluourouracil uma das principais drogas usadas no tratamento adjuvante e paliativo dessa doença. A toxicidade da quimioterapia e as alterações de qualidade de vida, causadas pela própria doença e pelo tratamento, são motivo de muitos estudos. OBJETIVO: Avaliar nos doentes com câncer colorretal em tratamento quimioterápico, a toxicidade e possíveis alterações da qualidade de vida. MÉTODOS: Durante o período de março de 2001 a maio de 2003 no Ambulatório de Oncologia da Disciplina de Gastroenterologia Clínica da Universidade Federal de São Paulo, foram acompanhados 45 pacientes com câncer colorretal em tratamento quimioterápico adjuvante ou paliativo com 5-fluourouracil e ácido folínico durante seis ciclos. A toxicidade gastrointestinal e hematológica foi analisada utilizando-se as Recomendações para a Graduação da Toxicidade Aguda e Subaguda. Após o término de cada ciclo quimioterápico, os resultados foram anotados de acordo com os respectivos graus que variaram entre 0 e 4. A qualidade de vida foi pesquisada pelo questionário WHOQOL bref (World Health Organization Quality of Life) que consta de 26 questões e é composto por 4 domínios: físico, psicológico, relações sociais e meio ambiente, no início, no 3° e no 6° ciclo de tratamento. RESULTADOS: Entre os 45 pacientes, 28 eram do sexo masculino, a média de idade foi de 58,4 anos (34 a 79 anos). Segundo a classificação da União Internacional Contra o Câncer, 34 (75,6 por cento) eram estádio II ou III e 11 estádio IV (24,4 por cento). Quanto à localização, 64,4 por cento eram de cólon. Em 57,7 por cento a quimioterapia foi adjuvante e nos demais paliativa. As toxicidades mais comumente encontradas foram náuseas (42 por cento), diarréia (38 por cento) e neutropenia (15,7 por cento). Não houve diferença significante entre os graus de toxicidade nos diferentes ciclos, assim como entre os doentes em tratamento adjuvante ou paliativo. Quanto à qualidade de vida foram observadas alterações significantes nos domínios físico e psicológico quando comparadas a primeira com a segunda ou a primeira com a terceira aplicação do questionário. Não foi encontrada alteração da qualidade de vida entre os doentes em quimioterapia adjuvante quando comparada aos em tratamento paliativo. Independente da indicação terapêutica, a média dos escores de qualidade de vida diminuiu em relação aos domínios físico e social na terceira aplicação do teste. CONCLUSÃO: As toxicidades gastrointestinais foram mais freqüentes que as hematológicas com o esquema utilizado. A qualidade de vida diminuiu após o início da quimioterapia em relação à atividade física e psicológica. No estudo da média dos escores observou-se queda dos mesmos nos domínios físico e social. A análise do questionário não mostrou alteração de qualidade vida quando comparados os doentes em tratamento paliativo com os em adjuvância.

BACKGROUND: The colorectal cancer is the fourth cause of cancer in Brazil and 5-fluorouracil is the drug most commonly used in the adjuvant or palliative treatment of this disease. AIM - Evaluating in patients with colorectal cancer and chemotherapy, the toxicity and the quality of life. PATIENTS AND METHODS: From March 2001 and May 2003, 45 patients treated with colorectal cancer treated with 5-fluourouracil and folinic acid were followed closely during six cycles. The gastrointestinal and hematologic toxicity was analysed making use of the chart "Recommendations for the Graduation of Acute and Subacute Toxicity". After the end of each cycle of chemotherapy, the results were registered according to the respectives degrees that vary from 0 to 4. The quality of life was researched through the WHOQOL bref (World Health Organization Quality of Life) questionary that consists of 26 questions and 4 domains: physical, psychological, social relations and environmental, in the beginning, on the 3rd and 6th cycles of treatment. RESULTS: Among the 45 patients, 28 were male, the average age was 58.4 years old (from 34 to 79 years old). According to the International Union Against Cancer classification, 34 patients (75.6 percent) had tumors stage II or III and 11 had tumors stage IV (24.4 percent), 64.4 percent were in the colon. In 57.7 percent the chemotherapy was adjuvant and in the others palliative. The toxicities more commonly found were nauseas (42 percent), diarrhea (38 percent), and neutropenia (15.7 percent). There was no significant difference among the degrees of toxicity in the different cycles as well as among the patients in adjuvant or palliative treatment. Significant alterations was found among the quality of life in the physical and psychological domains when the 1st and the 2nd or the 1st and the 3rd application of the test were done. Alterations of the quality of life were also found in the social domain when the first evaluation was compared with the last one. There was no difference between the quality of life and the treatment.

role of gemcitabine and cisplatin as first line therapy in patients with advanced ovarian carcinoma

This study included 40 patients with histopathologically proved advanced stages III and IV ovarian carcinoma according to 1998 criteria of International Federation of Gynecology and Obstetrics [FIGO] staging system. Patients were divided into two groups: Group I: a prospectively studied group of 20 previously untreated patients, seen during the period from December 1999 to December 2000, who received cisplatin [100mg/m[2]] day I and gemcitabine [1250mg/m[2]] day and day 8 and the cycle was repeated every 21 days. Group II: a retrospectively 20 patients, fulfilling the same eligibility criteria, who received cisplatin [100mg/m[2]] and cyclophosphamide [750mg/m[2]], both in day I and the cycle was repeated every 21 days. All patients in both groups received a total of six courses of treatment and the response was determined by clinical examination as well as pelvi-abdominal ultrasound, and pelvi-abdominal computed tomography. Complete response was achieved in 35% of cases in group I vs 15% in group II, while partial response was obtained in 35% in both groups. There were no statistical significant difference between overall response rate [O.R.R] in both groups [X2 = 3.86, P 0.277]. Patients who received gemcitabine/ cisplatin combination chemotherapy showed less anemia and less renal toxicity with better tolerance than the cyclophosphamide / cisplatin arm. There were no statistical significant difference between overall survival [O.S] in both arms, however the progression free survival [P.F.S] was better in group I and reached the level of significance compared to group II [P=0.03]

5-fluorouracil (5-FU) induces the formation of giant cells and sloughing of seminiferous epithelium in the rat testis.

The chemotherapeutic agent, 5-fluorouracil (5-FU) has been widely used in the treatment of a variety of cancers. Its effect on the testis has not been substantially studied. Present study was conducted to evaluate the gonadotoxicity of 5-FU in male albino rats. Animals were injected with single dose of 5-FU (10, 50 and 100 mg/kg, i.p.) and sampled on 1, 3, 15 and 30 day post exposure. Animals were anaesthetised, testes were perfusion fixed by Bouin's fluid. Five micron thick paraffin sections were stained with haematoxylin and eosin. Slides were screened for the incidence of partially and extensively sloughed tubules. Data were analysed by Mann Whitney 'U' test. Only 100 mg/kg induced multinucleated cells on 3rd day. All doses of 5-FU induced sloughing of the seminiferous epithelium. Maximum number of partially sloughed tubules were seen on third day. Partial sloughing was not dose dependent except on 15th day. The extensive sloughing was dose dependent except on 30th day. The result indicates that all the doses of 5-FU tested in this study cause sloughing of epithelium and only 100 mg/kg induces the formation of giant cells on third day.