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Different Molecular Pathways (different + molecular_pathway)
Selected AbstractsInterstrand crosslink inducing agents in pretransplant conditioning therapy for hematologic malignanciesENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 6 2010Benigno C. Valdez Abstract Despite successful molecularly targeted, highly specific, therapies for hematologic malignancies, the DNA interstrand crosslinking agents, which are among the oldest and least specific cytotoxic drugs, still have an important role. This is particularly true in stem cell transplantation, where virtually every patient receives conditioning therapy with a DNA-alkylating agent-based program. However, due to concern about serious additive toxicities with combinations of different alkylating drugs, the last several years have seen nucleoside analogs, whose cytotoxic action follows vastly different molecular pathways, introduced in combination with alkylating agents. The mechanistic differences paired with different metabolic pathways for the respective drugs have clinically translated into increased safety without appreciable loss of antileukemic activity. In this report, we review pre-clinical evidence for synergistic antileukemic activity when nucleoside analog(s) and DNA-alkylating agent(s) are combined in the most appropriate manner(s), without a measurable decrease in clinical efficacy compared with the more established alkylating agent combinations. Data from our own laboratory using combinations of fludarabine, clofarabine, and busulfan as prototype representatives for these respective classes of cytotoxic agents are combined with information from other investigators to explain how the observed molecular events will result in greatly enhanced synergistic cytotoxicity. We further present possible mechanistic pathways for such desirable cytotoxic synergism. Finally, we propose how this information-backed hypothesis can be incorporated in the design of the next generation conditioning therapy programs in stem cell transplantation to optimize antileukemic efficacy while still safeguarding patient safety. Environ. Mol. Mutagen., 2010. © 2010 Wiley-Liss, Inc. [source] Chronic erythropoietin treatment affects different molecular pathways of diabetic cardiomyopathy in mouseEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 9 2009N. Shushakova Abstract Background, Recent studies in mice experimental models with acute ischaemic injury revealed that erythropoietin (EPO) has numerous tissue-protective effects in the heart, brain and kidneys. We therefore explored the tissue-protective properties of chronic EPO treatment in an experimental model of the db/db mouse with diabetic heart injury. Material and methods, We randomly treated 11 db/db mice with placebo (saline), 0·4 ,g of the continuous erythropoietin receptor activator (CERA) per week (n = 11) or 1·2 ,g CERA per week (n = 11) for 14 weeks, and analysed cardiac tissue. The lower CERA dose was a non-haematologically effective dose, whereas the second increased the haematocrit. Results, Compared with mice in the placebo group, CERA-treated mice had a reduction in TGF-,1 and collagen I expression in cardiac tissue (P < 0·01 vs. higher dose CERA). In addition, an increased expression of the pro-survival intracellular pathway p-AKT was observed (P < 0·05 vs. higher dose CERA). The values for the lower C.E.R.A had an intermediate nonsignificant effect. Furthermore, we were able to show that atrial natriuretic peptide (ANP) expression was increased in both CERA groups. Conclusions, Chronic treatment with CERA protects cardiac tissue in diabetic animals, i.e. it inhibits molecular pathways of cardiac fibrosis, and the effects are dose-dependent. [source] Genistein induces cell growth inhibition in prostate cancer through the suppression of telomerase activityINTERNATIONAL JOURNAL OF UROLOGY, Issue 1 2005HIDEKI OUCHI Abstract Aim:, To clarify the mechanism of the anticancer effect of genistein, we examined the effect of genistein on telomerase activity in prostate cancer cells. We hypothesized that genistein may exert its anticancer effect by modifying telomerase activity in prostate cancer cells. Methods:, Prostate cancer (LNCaP) cells were cultured with genistein and the number of viable cells was counted. Growth medium was also collected to measure prostate-specific antigen (PSA) concentration. Polymerase chain reaction (PCR)-based telomeric repeat amplification protocol (TRAP) assay and reverse transcriptase (RT)-PCR analysis were performed to investigate telomerase activity and the expression of human telomerase reverse transcriptase (hTERT), c-myc and p21 mRNA. To examine the possibility that hTERT transcriptional activity is modulated by genistein, transient cell transfection studies were performed by using luciferase reporter assay. Telomere repeat amplification protocol (TRAP) assay and PCR analysis of hTERT were performed in androgen independent cells, DU-145. Results:, Cell growth of LNCaP was inhibited by genistein and PSA secretion was similarly reduced. In TRAP assay, the telomerase activity of LNCaP cells was reduced by genistein. Reverse transcriptase-PCR analysis revealed that the expression of hTERT and c-myc mRNA was down-regulated by genistein, whereas p21 mRNA increased in response to genistein. Luciferase reporter assay revealed that genistein reduced the transcriptional activity of hTERT. In DU-145 cells, telomerase activity and the expression of hTERT mRNA were also reduced by genistein. Conclusion:, The current study elucidated the molecular mechanism of cell growth inhibition by genistein. The antiproliferative effects of genistein seem to be exerted on the hTERT transcriptional activity via different molecular pathways. [source] Molecular mechanisms of UV-induced apoptosisPHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 5 2000D. Kulms Sunburn cells, single standing cells with typical morphologic features occurring in UV-exposed skin, have been recognized as keratinocytes undergoing apoptosis following UV irradiation. Induction of apoptosis following UV exposure appears to be a protective mechanism, getting rid off severely damaged cells that bear the risk of malignant transformation. UV-mediated apoptosis is a highly complex process in which different molecular pathways are involved. These include DNA damage, activation of the tumor suppressor gene p53, triggering of cell death receptors either directly by UV or by autocrine release of death ligands, mitochondrial damage and cytochrome C release. Detailed knowledge about the interplay between these pathways will increase our understanding of photocarcinogenesis. This review briefly discusses recent findings concerning the molecular mechanisms underlying UV-induced apoptosis. [source] Ageing in Plants: Conserved Strategies and Novel PathwaysPLANT BIOLOGY, Issue 5 2003H.-C. Jing Abstract: Ageing increases chaos and entropy and ultimately leads to the death of living organisms. Nevertheless, single gene mutations substantially alter lifespan, revealing that ageing is subject to genetic control. In higher plants, ageing is most obviously manifested by the senescence of leaves, and recent molecular genetic studies, in particular the isolation of Arabidopsis mutants with altered leaf senescence, have greatly advanced our understanding of ageing regulation in plants. This paper provides an overview of the identified genes and their respective molecular pathways. Hormones, metabolic flux, reactive oxygen species and protein degradation are prominent strategies employed by plants to control leaf senescence. Plants predominantly use similar ageing-regulating strategies as yeast and animals but have evolved different molecular pathways. The senescence window concept is proposed to describe the age-dependent actions of the regulatory genes. It is concluded that the similarities and differences in ageing between plants and other organisms are deeply rooted in the evolution of ageing and we hope to stimulate discussion and research in the fascinating field of leaf senescence. [source] Evidence that dysregulated DNA mismatch repair characterizes human nonmelanoma skin cancerBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2008L.C. Young Summary Background, In addition to an established role in the repair of postreplicative DNA errors, DNA mismatch repair (MMR) proteins also contribute to cellular responses to exogenous DNA damage. Previously, we have shown that Msh2 -null mice display increased sensitivity to ultraviolet (UV) B-induced tumorigenesis, but squamous cell carcinomas (SCC) generated are microsatellite stable, suggesting a role for MMR other than postreplicative repair in UV-induced cutaneous tumour formation. Objectives, We questioned whether there was evidence of MMR dysfunction in human SCC, thus validating the mouse models of MMR-dependent UVB-induced skin cancer. Methods, Using tissue microarrays we examined both nuclear and cytoplasmic levels of MMR proteins MSH2, MSH6, MSH3, MLH1 and PMS2 in more than 200 cases of cutaneous SCC and basal cell carcinoma (BCC). Results, We found that subsets of these 10 MMR protein measures were increased in nonmelanoma skin cancer (NMSC) compared with normal epidermal samples; this was particularly true of SCC. In fact, based on post hoc tests and MMR protein distribution patterns, BCC was distinct from SCC. With the exception of nuclear MSH2, the BCC had lower levels of identified MMR protein measures than SCC. We believe this to be important because not only is SCC more aggressive than BCC, but evidence suggests that these two NMSC subtypes arise through different molecular pathways. Conclusions, In combination with previously established roles for MMR proteins in response to UVB-induced DNA damage, our data point towards an expanded perspective of the importance of MMR proteins in the suppression of UVB-induced tumorigenesis and, potentially, tumour behaviour. [source] The APC/,-catenin pathway in ulcerative colitis,related colorectal carcinomasCANCER, Issue 5 2002A mutational analysis Abstract BACKGROUND Although the APC/,-catenin pathway is known to play a crucial role in sporadic colorectal carcinogenesis, its influence on ulcerative colitis (UC),related neoplastic progression is unknown. To elucidate the role of the APC-/,-catenin pathway in UC-related carcinogenesis, the authors identified APC and ,-catenin mutations in a set of UC-related and sporadic colorectal carcinomas. METHODS The mutational cluster region of APC (codon 1267 to 1529) and exon 3 of the ,-catenin were directly sequenced. RESULTS Only 1 of 30 UC-related tumors (3%) showed an APC mutation whereas 11 of the 42 sporadic carcinomas (26%) had mutations within the mutational cluster region. Within the sporadic carcinoma group, only 8% of the right-sided carcinomas showed APC mutations whereas 50% of the left-sided carcinomas had mutations within the mutational cluster region. None of the tumors in either group showed a ,-catenin mutation. CONCLUSIONS Mutations of the APC and ,-catenin are rare in UC-related tumors. These genes may be altered because of mutations outside the regions studied, or by epigenetic silencing. Alternatively, other proteins involved in the APC/,-catenin signaling cascade may be altered, or this pathway may be involved infrequently in UC-related carcinogenesis. The significant difference in frequency of APC mutations between right- and left-sided sporadic tumors suggests different molecular pathways in these two tumor sites. Cancer 2002;94:1421,7. © 2002 American Cancer Society. DOI 10.1002/cncr.10334 [source] | |||||||||||||