Role of wild type p53 and double suicide genes in interventional therapy of liver cancer in rabbits / Papel do p53 selvagem e do duplo genes suicidas na terapia intervencionista do câncer de fígado em coelhos

PURPOSE: To investigate the feasibility of interventional lipiodol embolism and multigene therapy in combination with focal chemotherapy in the treatment of VX2 liver cancer in rabbits. METHODS: Forty five rabbits with cancer larger than 2cm in diameter were randomly divided into five groups (n=9 per group). In Group 1, animals were treated with 0.9% sodium chloride. In Group 2, animals received lipiodol embolism. In Group 3, animals received lipiodol embolism and p53 gene therapy. In Group 4, animals received lipiodol embolism and TK/CD gene therapy. In Group 5, animals received lipiodol embolism and p53 and TK/CD gene therapy. Ultrasonography and CT were performed before and at ten days after interventional therapy. RESULTS: The VX2 model of liver cancer was successfully established in rabbits and interventional therapy smoothly performed. At ten days after interventional therapy, significant difference in the tumor volume was noted among five groups (p<0.05) and different treatments could inhibit the cancer growth. The inhibition of cancer growth was the most evident in the Group 5. Factorial analysis revealed gene therapy with p53 or TK/CD and lipiodol embolism independently exert significantly inhibitory effect on cancer growth. In addition, the suppression on tumor growth rate was the most obvious in the Group 5. CONCLUSIONS: Combination of gene therapy with lipiodol embolism can effectively inhibit the cancer growth and prolong the survival time. These findings demonstrate the effectiveness of multigene therapy in combination with lipiodol embolism in the treatment of liver cancer.

OBJETIVO: Investigar a possibilidade de terapia multigênica e intervenção por embolização com lipiodol em combinação com quimioterapia focal no tratamento de câncer de fígado VX2 em coelhos. MÉTODOS: Quarenta e cinco coelhos com câncer maior do que 2cm de diâmetro foram distribuídos, aleatoriamente, em cinco grupos (n=9 por grupo). Grupo 1: animais foram tratados com cloreto de sódio 0,9% e no grupo 2 os animais receberam embolização com lipidol. Grupo 3: animais receberam embolização com lipiodol e terapia do gene p53 e grupo 4 animais receberam embolização com lipiodol e terapia do gene TK/CD. Grupo 5: animais receberam embolização com lipiodol e terapia do gene p53 e do gene TK/CD. Ultrassonografia e tomografia computadorizada foram realizadas antes e dez dias após a intervenção terapêutica. RESULTADOS: O modelo VX2 de câncer de fígado foi estabelecido com sucesso em coelhos e a terapia intervencionista foi bem executada. Dez dias após a intervenção terapêutica, uma diferença significativa no volume do tumor foi observada entre os cinco grupos (p<0,05) e diferentes tratamentos poderiam inibir o crescimento do câncer. A inibição do crescimento do cancer foi mais evidente no grupo 5. Análise fatorial revelou que a terapia com gene p53 ou TK/CD e embolia por lipiodol independentemente exerce um efeito inibidor significativo sobre o crescimento do câncer. Além disso, a supressão da taxa de crescimento do tumor foi mais evidente no Grupo 5. CONCLUSÕES: A combinação de terapia gênica com embolização com lipiodol pode inibir efetivamente o crescimento do câncer e prolongar o tempo de sobrevida. Estes resultados demonstram a eficácia da terapia multigênica em combinação com embolização com lipidol no tratamento de câncer hepático.

Gene and environment interaction in familial suicidal behavior: a single family with 4 committed suicides

Family history of suicide is among the strongest predictors of suicide risk. From the context of gene by environment interactions, this manuscript presents a case study of the "M" family, which experienced 4 committed suicides within a short time period. Over the course of 5 years, the father and 3 sons committed suicide. Suicidal ideations developed in several other members of the family. The family's suicide risk appears to have stemmed from both environmental and genetic factors, and likely from an interactive effect between both. Environmental factors included low level of education, opium dependency among male family members, unemployment, and poverty, and limited access to mental health services. Genotype analyses of A218C polymorphism among surviving family members revealed that all individuals were associated with the gene variation [genotypes CC and AC] in tryptophan hydroxylase. The genetic by environmental interaction influence is discussed

Effect of suicide gene therapy in combination with immunotherapy on antitumour immune response & tumour regression in a xenograft mouse model for head & neck squamous cell carcinoma.

Background & objectives: Prodrug activation strategy as well as immunotherapy have been widely used for cancer gene therapy. In the present study, using a head and neck squamous cell carcinoma (HNSCC) xenograft nude mouse model, we have investigated whether the two therapies in combination could improve tumour cell kill. We also investigated induction of immune effector cells viz., NK (DX5+) and DC (CD11c+) in vivo, post-combination gene therapy. Methods: A retroviral vector producing cell line (PLTK47.1 VPC) carrying Herpes simplex virus thymidine kinase gene (HSVtk) was used for intratumoural injection into NT8e xenograft tumours followed by the prodrug ganciclovir (GCV). IL-2 plasmid DNA was injected intramuscularly. Immune cells were analyzed by flow-cytometry. Non parametric ANOVA was performed with Kruskal Wallis test. Results: IL-2 could induce proliferation of both NK cells (DX5+) and dendritic cells (CD11c+) in vivo. Apoptosis was higher in combination therapy group as compared to HSVtk/GCV alone or IL-2 alone and was mediated through caspase-3 dependent pathway. Significant reduction in tumour volume was seen in all 3 treatment arms as compared to controls. Interpretation & conclusions: Combination of suicide gene therapy and immunotherapy leads to successful tumour regression in a HNSCC xenograft mouse model. Immunotherapy could help in a systemic long lived anti-tumour immune response which would prove powerful for the treatment of metastatic cancers, and also for minimal residual disease. The results of this study may form the basis for Phase 1 clinical trials.