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1.
It has been previously shown that estrogens may exert their action on human breast cancer cells through coordinated control of secreted growth factors which act in an autocrine and paracrine fashion. Growth stimulation of the androgen receptor negative prostate carcinoma cell line DU-145 by dihydrotestosterone in the presence of the androgen-responsive human prostate carcinoma cell line LNCaP now indicates that androgens may regulate growth of prostate carcinoma cells through related mechanisms. A variety of androgen-regulated growth modulatory activities with autocrine and paracrine potential can be detected in conditioned media from LNCaP cells partially purified by ion exchange chromatography. Androgen-induced growth of LNCaP cells is partially inhibited by the polyanions suramin and dextran sulfates which antagonize growth factor action. These data suggest the existence of at least two different mechanisms of growth regulation by androgen which can be distinguished by their different sensitivity to growth factor inhibitory agents. We conclude that the combination of antipeptidergic substances and androgen withdrawal would represent a new and promising strategy for treatment of human prostate cancer.  相似文献   

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RNA interference (RNAi) has emerged as one of the most important discoveries of the last years in the field of molecular biology. Following clarification of this highly conserved endogenous gene silencing mechanism, RNAi has largely been exploited as a powerful tool to uncover the function of specific genes and to understand the effects of selective gene silencing in mammalian cells both in vitro and in vivo. RNAi can be induced by direct introduction of chemically synthesized siRNAs into the cell or by the use of plasmid and viral vectors encoding for siRNA allowing a more stable RNA knockdown. Potential application of this technique both as a research tool and for therapeutic purposes has led to an extensive effort to overcome some critical constraints which may limit its successful application in vivo, including off-target and non-specific effects, as well as the relatively poor stability of siRNA. This review provides a brief overview of the RNAi mechanism and of its application in preclinical animal models of cancer.  相似文献   

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This comprehensive review addresses most organs at risk involved in planning optimization for prostate cancer. It can be considered an update of a previous educational review that was published in 2009 (Fiorino et al., 2009).The literature was reviewed based on PubMed and MEDLINE database searches (from January 2009 up to September 2015), including papers in press; for each section/subsection, key title words were used and possibly combined with other more general key-words (such as radiotherapy, dose-volume effects, NTCP, DVH, and predictive model). Publications generally dealing with toxicity without any association with dose–volume effects or correlations with clinical risk factors were disregarded, being outside the aim of the review.A focus was on external beam radiotherapy, including post-prostatectomy, with conventional fractionation or moderate hypofractionation (<4 Gy/fraction); extreme hypofractionation is the topic of another paper in this special issue. Gastrointestinal and urinary toxicity are the most investigated endpoints, with quantitative data published in the last 5 years suggesting both a dose–response relationship and the existence of a number of clinical/patient related risk factors acting as dose–response modifiers. Some results on erectile dysfunction, bowel toxicity and hematological toxicity are also presented.  相似文献   

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Apoptosis - Activating molecule in Beclin-1-regulated autophagy protein 1 (Ambra1) is well known to mediate the autophagy process and promote the formation of autophagosomes. In addition, Ambra1 is...  相似文献   

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Tumor growth and progression depends on tumor angiogenesis, the growth of tumor blood vessels, therefore, targeting tumor angiogenesis is a very promising approach for controlling tumor growth and/or causing regression. Tumor blood vessels have been recognized as a critical component of radiation response to the point of being independent of tumor oxygenation during radiation. An anti-angiogenic approach has been considered less likely to develop drug resistance. But recent findings suggest that anti-angiogenesis causes hypoxia that selects tumor cells (due to genetic instability) that are less dependent on blood supply and leads to drug resistance. The approach of combination of anti-angiogenesis with ionizing radiation by targeting both endothelial and tumor cells should minimize this possibility. The combination may produce a synergistic anti-tumor effect.  相似文献   

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This review outlines the principal limitations of the mechanisms of active cell death (ACD, apoptosis) as the basis of tumorigenesis and the rationale of almost all therapies of malignancy. The concentration of cancer therapy in the direction of ACD induction is presented as both the result of progressive understanding of the mechanisms of apoptosis and that of the favourable tumor environment for ACD signal transmission. The latter property induces the by-stander killing of cancer cells, a fundamental mechanism because efficiency of all known methods of cancer treatment is far below 100%. Finally, recent results and hypotheses regarding cancer gene therapy based on final inductors of apoptosis and endogeneous ACD inhibitors in tumors are evaluated.  相似文献   

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RECKing MMP function: implications for cancer development   总被引:19,自引:0,他引:19  
Cancer is a multistage process requiring progressive genetic and epigenetic changes in neoplastic and responding stromal cells. Many alterations that occur during the process of malignant progression are regulated by the matrix metalloproteinase (MMP) family of extracellular proteases and their endogenous inhibitors. Recent work has identified a new cell-surface inhibitor of MMPs - RECK. RECK regulates MMP-induced pericellular signaling cascades during embryogenesis and tumorigenesis. Homozygous loss of RECK results in embryonic lethality and attenuated tumor development in adults - thus providing further support for an efficacious role for protease inhibitors as anticancer therapeutics.  相似文献   

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Cell Biology and Toxicology - Regardless of the recent advances in therapeutic developments, cancer is still among the primary causes of death globally, indicating the need for alternative...  相似文献   

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HLA expression in cancer: implications for T cell-based immunotherapy   总被引:8,自引:0,他引:8  
Sette A  Chesnut R  Fikes J 《Immunogenetics》2001,53(4):255-263
HLA class I expression is altered in a significant fraction of the tumor types reviewed here, reflecting either immune pressure or, simply, the accumulation of pathological changes and alterations. However, in all tumor types analyzed, a majority of the tumors express HLA class I. with a general tendency for the more severe alterations to be found in later-stage and less differentiated tumors. These results are encouraging for the development of specific immunotherapies, especially considering that (1) the relatively low sensitivity of immunohistochemical techniques might underestimate HLA expression in tumors, (2) class I expression can be induced in tumor cells as a result of local inflammation and lymphokine release, and (3) class I-negative cells would be predicted to be sensitive to Iysis by natural killer cells.  相似文献   

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A rapid growth of the coronary vasculature occurs during prenatal and early postnatal periods as precursor cells from the epi- and sub-epicardium differentiate, migrate and form vascular structures (vasculogenesis) which then fuse, branch and in some cases recruit cells to form three tunics (angiogenesis). These processes are tightly controlled by temporally and spatially expressed growth factors which are stimulated by metabolic and mechanical factors. The process of angiogenesis in the myocardium is not limited to developmental periods of life, but may occur when the heart is challenged by enhanced loading conditions or during hypoxia or ischemia. This review focuses on the activation of growth factors by metabolic and mechanical stimuli in the developing heart and in the adult heart undergoing adaptive responses. Experimental studies support the hypotheses that both metabolic (hypoxia) and mechanical (stretch) factors serve as powerful stimuli for the up-regulation of growth factors which facilitate angiogenesis and arteriogenesis. Both hypoxia and stretch are powerful inducers of VEGF and its receptors, and provide for paracrine and autocrine signaling. In addition to the VEGF family, bFGF and angiopoietins play major roles in myocardial vascularization. Sufficient evidence supports the hypothesis that mechanical (e.g., bradycardia) and metabolic (e.g., thyroxine analogs) may provide effective non-invasive angiogenic therapies for the ischemic and post-infarcted heart. (Mol Cell Biochem 264: 3–11, 2004)  相似文献   

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Pro-apoptotic role of NF-kappaB: implications for cancer therapy   总被引:2,自引:0,他引:2  
Nuclear factor-kappaB (NF-kappaB) is generally viewed as anti-apoptotic and oncogenic, leading to a quest for its inhibitors. However, recent evidence suggests that in some situations NF-kappaB may promote apoptosis. Depending on the specific cell type and the stimulus involved, NF-kappaB activation may lead to either anti- or pro-apoptotic response. Both these effects can be mediated by NF-kappaB in a context-dependent manner by selectively regulating its target genes. In this review, we discuss the evidence for NF-kappaB's pro-apoptotic role and explore the possible mechanisms behind it. We emphasize that rather than trying to inhibit NF-kappaB in cancer therapy, agents should be developed to unleash its pro-apoptotic ability.  相似文献   

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A rapid growth of the coronary vasculature occurs during prenatal and early postnatal periods as precursor cells from the epi- and sub-epicardium differentiate, migrate and form vascular structures (vasculogenesis) which then fuse, branch and in some cases recruit cells to form three tunics (angiogenesis). These processes are tightly controlled by temporally and spatially expressed growth factors which are stimulated by metabolic and mechanical factors. The process of angiogenesis in the myocardium is not limited to developmental periods of life, but may occur when the heart is challenged by enhanced loading conditions or during hypoxia or ischemia. This review focuses on the activation of growth factors by metabolic and mechanical stimuli in the developing heart and in the adult heart undergoing adaptive responses. Experimental studies support the hypotheses that both metabolic (hypoxia) and mechanical (stretch) factors serve as powerful stimuli for the up-regulation of growth factors which facilitate angiogenesis and arteriogenesis. Both hypoxia and stretch are powerful inducers of VEGF and its receptors, and provide for paracrine and autocrine signaling. In addition to the VEGF family, bFGF and angiopoietins play major roles in myocardial vascularization. Sufficient evidence supports the hypothesis that mechanical (e.g., bradycardia) and metabolic (e.g., thyroxine analogs) may provide effective non-invasive angiogenic therapies for the ischemic and post-infarcted heart.  相似文献   

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The ability of a number of flavonoids to induce glutathione (GSH) depletion was measured in lung (A549), myeloid (HL-60), and prostate (PC-3) human tumor cells. The hydroxychalcone (2'-HC) and the dihydroxychalcones (2',2-, 2',3-, 2',4-, and 2',5'-DHC) were the most effective in A549 and HL-60 cells, depleting more than 50% of intracellular GSH within 4 h of exposure at 25 microM. In contrast, the flavones chrysin and apigenin were the most effective in PC-3 cells, depleting 50-70% of intracellular GSH within 24 h of exposure at 25 microM. In general, these flavonoids were more effective than three classical substrates of multidrug resistance protein 1 (MK-571, indomethacin, and verapamil). Prototypic flavonoids (2',5'-DHC and chrysin) were subsequently tested for their abilities to potentiate the toxicities of prooxidants (etoposide, rotenone, 2-methoxyestradiol, and curcumin). In A549 cells, 2',5'-DHC potentiated the cytotoxicities of rotenone, 2-methoxyestradiol, and curcumin, but not etoposide. In HL-60 and PC-3 cells, chrysin potentiated the cytotoxicity of curcumin, cytotoxicity that was attenuated by the catalytic antioxidant manganese(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP). Assessments of mitochondrial GSH levels mitochondrial membrane potential and cytochrome c release showed that the potentiation effects induced by 2',5'-DHC and chrysin involve mitochondrial dysfunction.  相似文献   

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Intensity modulated radiation therapy (IMRT) allows physicians to deliver higher conformal doses to the tumour, while avoiding adjacent structures. As a result the probability of tumour control is higher and toxicity may be reduced. However, implementation of IMRT is highly complex and requires a rigorous quality assurance (QA) program both before and during treatment. The present article describes the process of implementing IMRT for localized prostate cancer in a radiation therapy department. In our experience, IMRT implementation requires careful planning due to the need to simultaneously implement specialized software, multifaceted QA programs, and training of the multidisciplinary team. Establishing standardized protocols and ensuring close collaboration between a multidisciplinary team is challenging but essential.  相似文献   

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