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Candidate Agent (candidate + agent)
Selected AbstractsCandidate therapeutic agents for hepatocellular cancer can be identified from phenotype-associated gene expression signaturesCANCER, Issue 16 2009Chiara Braconi MD Abstract BACKGROUND: The presence of vascular invasion in hepatocellular cancer (HCC) correlates with prognosis, and is a critical determinant of both the therapeutic approach and the recurrence or intrahepatic metastases. The authors sought to identify candidate therapeutic agents capable of targeting the invasive phenotype in HCC. METHODS: A gene expression signature associated with vascular invasion derived from 81 human cases of HCC was used to screen a database of 453 genomic profiles associated with 164 bioactive molecules using the connectivity map. Candidate agents were identified by their inverse correlation to the query gene signature. The efficacy of the candidate agents to target invasion was experimentally verified in PLC/PRF-5 and HepG2 HCC cells. RESULTS: The gene signature associated with vascular invasion in HCC comprised of 47 up-regulated and 26 down-regulated genes. Computational bioinformatics analysis revealed several putative candidates, including resveratrol and 17-allylamino-geldanamycin (17-AAG). Both of these agents reduced HCC cell invasion at noncytotoxic concentrations. 17-AAG, a heat shock protein 90 (HSP-90) inhibitor, was shown to modulate the expression of several diverse cancer-associated genes, including ADAMTS1, part of the query signature, and maspin, an HSP-90,associated protein with a tumor suppressor role in HCC. CONCLUSIONS: Candidates for further evaluation as therapies to limit invasion in HCC have been identified using a computational bioinformatics analysis of phenotype-associated gene expression. Phenotype targeting using genomic profiling is a rational approach for drug discovery. Therapeutic strategies targeting a defined cancer-associated phenotype can be identified without a detailed knowledge of individual downstream targets. Cancer 2009. © 2009 American Cancer Society. [source] Biology and host specificity of Aulacobaris fallax (Coleoptera: Curculionidae), a potential biological control agent for dyer's woad, Isatis tinctoria (Brassicaceae) in North AmericaJOURNAL OF APPLIED ENTOMOLOGY, Issue 5 2009E. Gerber Abstract Dyer's woad, Isatis tinctoria, a plant of Eurasian origin is a problematic weed in western North America against which a classical biological weed control programme was initiated in 2004. Three European insect species were selected as candidate agents to control this invasive species, including the root-mining weevil Aulacobaris fallax. To determine its suitability as an agent, the biology and host specificity of A. fallax were studied in outdoor plots and in the field between 2004 and 2006 in its native European range. Aulacobaris fallax is a univoltine species that lays its eggs from March to August into leaf stalks and roots of dyer's woad. Larvae mine and pupate in the roots and adults emerge from August to October. Up to 62% of the dyer's woad plants at the field sites investigated were attacked by this weevil. In no-choice host-specificity tests, A. fallax attacked 16 out of 39 species and varieties within the Family Brassicaceae. Twelve of these are native to North America. In subsequent multiple-choice tests, seven species, all native to North America, suffered a similar level of attack as dyer's woad, while none of the European species were attacked. Our results demonstrate the importance of including test plant species that have not co-evolved with the respective candidate agent. In sum, we conclude that the risk of non-target effects is too high for A. fallax to be considered as a biological control agent for dyer's woad in the United States. [source] Vitamin D and systemic cancer: is this relevant to malignant melanoma?BRITISH JOURNAL OF DERMATOLOGY, Issue 2 2002J.E. Osborne Summary 1,25-dihydroxyvitamin D3[1,25(OH)2D3] is a well-known potent regulator of cell growth and differentiation and there is recent evidence of an effect on cell death, tumour invasion and angiogenesis, which makes it a candidate agent for cancer regulation. The classical synthetic pathway of 1,25(OH)2D3 involves 25- and 1,-hydroxylation of vitamin D3, in the liver and kidney, respectively, of absorbed or skin-synthesized vitamin D3. There is recent focus on the importance in growth control of local metabolism of 1,25(OH)2D3, which is a function of local tissue synthetic hydroxylases and particularly the principal catabolizing enzyme, 24-hydroxylase. The classical signalling pathway of 1,25(OH)2D3 employs the vitamin D nuclear receptor (VDR), which is a transcription factor for 1,25(OH)2D3 target genes. Effects of this pathway include inhibition of cellular growth and invasion. Cytoplasmic signalling pathways are increasingly being recognized, which similarly may regulate growth and differentiation but also apoptosis. 1,25(OH)2D3 has a major inhibitory effect on the G1/S checkpoint of the cell cycle by upregulating the cyclin dependent kinase inhibitors p27 and p21, and by inhibiting cyclin D1. Indirect mechanisms include upregulation of transforming growth factor-, and downregulation of the epidermal growth factor receptor. 1,25(OH)2D3 may induce apoptosis either indirectly through effects on the insulin-like growth receptor and tumour necrosis factor-, or more directly via the Bcl-2 family system, the ceramide pathway, the death receptors (e.g. Fas) and the stress-activated protein kinase pathways (Jun N terminal kinase and p38). Inhibition of tumour invasion and metastasis potential has been demonstrated and mechanisms include inhibition of serine proteinases, metalloproteinases and angiogenesis. The lines of evidence for an effect of vitamin D3 in systemic cancer are the laboratory demonstration of relevant effects on cellular growth, differentiation, apoptosis, malignant cell invasion and metastasis; epidemiological findings of an association of the occurrence and outcome of cancers with derangements of vitamin D3/1,25(OH)2D3 and the association of functional polymorphisms of the VDR with the occurrence of certain cancers. In addition, vitamin D3 analogues are being developed as cancer chemotherapy agents. There is accumulating evidence that the vitamin D3/1,25(OH)2D3/VDR axis is similarly important in malignant melanoma (MM). MM cells express the VDR, and the antiproliferative and prodifferentiation effects of 1,25(OH)2D3 have been shown in cultured melanocytes, MM cells and MM xenografts. Recently, an inhibitory effect on the spread of MM cells has been demonstrated, low serum levels of 1,25(OH)2D3 have been reported in MM patients and the VDR polymorphisms have been shown to be associated with both the occurrence and outcome of MM. The relationship between solar irradiation and MM is more complex than for the systemic cancers. As in other cancers, there is evidence of a protective effect of vitamin D3 in MM, but ultraviolet radiation, which is a principal source of vitamin D3, is mutagenic. Further work is necessary on the influence of serum vitamin D3 levels on the occurrence and prognosis of MM, the effects of sun protection measures on serum vitamin D3 levels in temperate climates and epidemiological studies on geographical factors and skin type on the prognosis of MM. Meanwhile, it would seem mandatory to ensure an adequate vitamin D3 status if sun exposure were seriously curtailed, certainly in relation to carcinoma of breast, prostate and colon and probably also MM. [source] Biology and host specificity of Aulacobaris fallax (Coleoptera: Curculionidae), a potential biological control agent for dyer's woad, Isatis tinctoria (Brassicaceae) in North AmericaJOURNAL OF APPLIED ENTOMOLOGY, Issue 5 2009E. Gerber Abstract Dyer's woad, Isatis tinctoria, a plant of Eurasian origin is a problematic weed in western North America against which a classical biological weed control programme was initiated in 2004. Three European insect species were selected as candidate agents to control this invasive species, including the root-mining weevil Aulacobaris fallax. To determine its suitability as an agent, the biology and host specificity of A. fallax were studied in outdoor plots and in the field between 2004 and 2006 in its native European range. Aulacobaris fallax is a univoltine species that lays its eggs from March to August into leaf stalks and roots of dyer's woad. Larvae mine and pupate in the roots and adults emerge from August to October. Up to 62% of the dyer's woad plants at the field sites investigated were attacked by this weevil. In no-choice host-specificity tests, A. fallax attacked 16 out of 39 species and varieties within the Family Brassicaceae. Twelve of these are native to North America. In subsequent multiple-choice tests, seven species, all native to North America, suffered a similar level of attack as dyer's woad, while none of the European species were attacked. Our results demonstrate the importance of including test plant species that have not co-evolved with the respective candidate agent. In sum, we conclude that the risk of non-target effects is too high for A. fallax to be considered as a biological control agent for dyer's woad in the United States. [source] Candidate therapeutic agents for hepatocellular cancer can be identified from phenotype-associated gene expression signaturesCANCER, Issue 16 2009Chiara Braconi MD Abstract BACKGROUND: The presence of vascular invasion in hepatocellular cancer (HCC) correlates with prognosis, and is a critical determinant of both the therapeutic approach and the recurrence or intrahepatic metastases. The authors sought to identify candidate therapeutic agents capable of targeting the invasive phenotype in HCC. METHODS: A gene expression signature associated with vascular invasion derived from 81 human cases of HCC was used to screen a database of 453 genomic profiles associated with 164 bioactive molecules using the connectivity map. Candidate agents were identified by their inverse correlation to the query gene signature. The efficacy of the candidate agents to target invasion was experimentally verified in PLC/PRF-5 and HepG2 HCC cells. RESULTS: The gene signature associated with vascular invasion in HCC comprised of 47 up-regulated and 26 down-regulated genes. Computational bioinformatics analysis revealed several putative candidates, including resveratrol and 17-allylamino-geldanamycin (17-AAG). Both of these agents reduced HCC cell invasion at noncytotoxic concentrations. 17-AAG, a heat shock protein 90 (HSP-90) inhibitor, was shown to modulate the expression of several diverse cancer-associated genes, including ADAMTS1, part of the query signature, and maspin, an HSP-90,associated protein with a tumor suppressor role in HCC. CONCLUSIONS: Candidates for further evaluation as therapies to limit invasion in HCC have been identified using a computational bioinformatics analysis of phenotype-associated gene expression. Phenotype targeting using genomic profiling is a rational approach for drug discovery. Therapeutic strategies targeting a defined cancer-associated phenotype can be identified without a detailed knowledge of individual downstream targets. Cancer 2009. © 2009 American Cancer Society. [source] | ||||||||||