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Tumour Cell Apoptosis (tumour + cell_apoptosi)

Distribution by Scientific Domains

Life Sciences	50%

Selected Abstracts

In vivo efficacy of HSV-TK transcriptionally targeted to the tumour vasculature is augmented by combination with cytotoxic chemotherapy

THE JOURNAL OF GENE MEDICINE, Issue 3 2005
Georgia Mavria
Abstract Background Retroviral vectors are suitable for targeting endothelial cells in the tumour neovasculature because of their intrinsic selectivity for proliferating cells. Previously, we inserted regulatory elements of the endothelial-specific prepro-endothelin-1 (ppET1) promoter in retroviral vectors to generate high-titre, replication-defective recombinant retroviruses that restricted gene expression to the vascular compartment of tumours. Methods A retroviral vector was generated in which expression of herpes simplex virus thymidine kinase (HSV-TK) was transcriptionally restricted to endothelial cells, under the control of a hybrid ppET-1 LTR. Xenograft tumour models were used to determine the efficacy of targeting HSV-TK to the tumour vasculature. Subsequently, vascular-targeted gene therapy was combined with chemotherapeutic agents. Results Breast or colorectal xenograft tumour growth was reduced and survival was increased in response to ganciclovir treatment. Treatment resulted in widespread vascular disruption and tumour cell apoptosis. In colorectal tumours, combination with irinotecan, a cytotoxic drug used to treat colorectal cancer, significantly increased survival compared to drug alone. No beneficial effect on survival was observed when combined with cisplatin, a cytotoxic drug not in clinical use for this tumour type. On the basis of their relative efficacies in vitro against tumour and endothelial cells, co-operativity with irinotecan likely derives from additionally targeting the peripheral tumour cells that survive the anti-vascular treatment. Conclusions We show that the ppET1-targeted vector is efficacious for therapeutic gene expression in vivo, validating a strategy targeted to tumour vasculature, and demonstrate that vascular targeting combined with appropriate chemotherapy is more effective than either therapy alone. Copyright © 2004 John Wiley & Sons, Ltd. [source]

Proapoptotic and antiapoptotic markers in cutaneous T-cell lymphoma skin infiltrates and lymphomatoid papulosis

BRITISH JOURNAL OF DERMATOLOGY, Issue 6 2001
H. Nevala
Background In cutaneous T-cell lymphoma (CTCL) lesions, both reactive T cells and malignant T cells intermingle. The disease progression is mostly slow. Recent evidence suggests that even if clinical remission is reached, malignant cells persist and a relapse follows sooner or later. To what extent tumour cell apoptosis occurs in the skin lesions either due to the reactive T cells or to therapeutic efforts is not known. Objectives To determine the extent of tumour cell apoptosis and the expression of proapoptotic and antiapoptotic markers in serial skin lesion samples from patients with CTCL, and to compare the findings with those in patients with lymphomatoid papulosis (LyP). Methods Thirty-four skin samples were obtained from 12 patients with CTCL at the time of diagnosis and at a mean of 1·6, 3 and 6 years later. The patients received psoralen plus ultraviolet A (PUVA), electron beam or cytostatic treatments. In addition, fresh post-treatment samples from three patients with CTCL undergoing PUVA therapy were obtained. For comparison, skin biopsies of five patients with LyP were studied. Immunohistochemical demonstration of the expression of the following markers was performed on formalin-fixed skin sections: Fas (CD95), Fas ligand (FasL), bcl-2, granzyme B, the tumour-suppressor protein PTEN and the effector caspase, caspase-3. The malignant cells were identified morphologically, and apoptotic cells were identified with the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling method on parallel sections. Results In untreated CTCL lesions, apoptotic lymphocytes were extremely rare, and no increase in the number of apoptotic cells was observed after any of the treatments used. In LyP, apoptotic cells were more frequent, comprising on average 5% of the infiltrate. The apoptosis-associated markers Fas, FasL, caspase-3 and granzyme B were expressed by morphologically neoplastic cells in CTCL and by large atypical cells in LyP, with no significant differences. However, only a few reactive cells in CTCL infiltrates expressed granzyme B while about 10% of the corresponding cells were positive in LyP. The expression of antiapoptotic bcl-2 was more frequent in CTCL than in LyP, while PTEN expression was high in both instances. The number of bcl-2+ cells tended to decrease after therapy. When comparing the findings between the first and the last samples, a decrease in the number of bcl-2+ cells and an increase in Fas+ cells was associated with disease progression, despite therapy, while the opposite was true for remissions. Conclusions Apoptosis was found to be a rare event in CTCL lesions irrespective of preceding therapy. During patient follow-up, no significant differences in the expression of apoptotic markers was observed while in most cases a lower level of antiapoptotic bcl-2 expression was observed after all types of therapies and in association with disease progression when compared with high expression in the untreated lesions. The absence of apoptosis and high expression of bcl-2 together with a low expression of apoptosis-inducing granzyme B in the reactive lymphocytes in CTCL could explain the chronic nature of the disease and the poor response to therapy, while the more frequent occurrence of granzyme B and apoptosis together with a lower level of expression of bcl-2 by the large atypical cells in LyP could contribute to the favourable outcome of the latter. [source]

Ecology-based screen identifies new metabolites from a Cordyceps -colonizing fungus as cancer cell proliferation inhibitors and apoptosis inducers

CELL PROLIFERATION, Issue 6 2009
Y. Chen
Objectives:, This study aims to identify new anti-cancer agents from Cordyceps -colonizing fungi, using an ecology-based approach. It also aims to explore their anti-cell proliferative mechanisms, and to evaluate their anti-tumour effects in vivo. Materials and methods:, Extracts from Cordyceps -colonizing fungi were tested on HeLa cells, and active extracts were separated to obtain anti-tumour metabolites; their structures were elucidated by mass and nuclear magnetic resonance spectroscopy. Cell cycle analysis was evaluated using flow cytometry. Tumour formation assays were performed using C57BL/6J mice. Results:, Based on ecological considerations, the selected extracts were subjected to initial anti-tumour screening. Bioassay-guided fractionation of the active extract afforded two new epipolythiodioxopiperazines, named gliocladicillins A (1) and B (2). (A) 1 and B (2) inhibited growth of HeLa, HepG2 and MCF-7 tumour cells. Further study demonstrated that both preparations arrested the cell cycle at G2/M phase in a dose-dependent manner, and induced apoptosis through up-regulation of expression of p53, p21, and cyclin B, and activation of caspases-8, -9 and -3. These data imply that gliocladicillins A (1) and B (2) induce tumour cell apoptosis through both extrinsic and intrinsic pathways. In addition, in vivo studies showed that they displayed significant inhibitory effects on cell population growth of melanoma B16 cells imlanted into immunodeficient mice. Conclusions:, Gliocladicillins A (1) and B (2) are effective anti-tumour agents in vitro and in vivo and should be further evaluated for their potential in clinical use. [source]