Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

These experiments were designed to test the role of the polyamine pathway in breast cancer progression utilizing an experimental system based on the development of ovary-independent rat mammary tumors and their sequential transplantation into syngeneic hosts. Three key enzymes involved in the PA biosynthetic/catabolic pathway (ornithine-decarboxylase (ODC), S-adenosylmethionine decarboxylase (SAMDC), and spermidine/spermine N'-acetyltransferase (SSAT)) were measured in tumors at different stages of progression. The most significant finding was the association between increased ODC activity and the acquisition of a hormone-independent, poorly differentiated phenotype. SSAT levels tended to be higher in hormone-independent tumors and, in this tumor category, they tended to be positively correlated with differentiation. However, significant interaction between hormone dependence and differentiation status on SSAT expression prevented reliable assessment of the possibly complex role of this enzyme in tumor progression. Neither hormone dependence nor differentiation status were correlated with SAMDC levels. We conclude that, among the three enzymes tested, ODC overexpression is the most significant alteration in the PA metabolic pathway associated with breast cancer progression in this experimental system.
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PMID:Involvement of the polyamine pathway in breast cancer progression. 775 60

In silico chemical library screening (virtual screening) was used to identify a novel lead compound capable of inhibiting S-adenosylmethionine decarboxylase (AdoMetDC). AdoMetDC is intimately involved in the biosynthesis of polyamines, which are essential for tumor progression and are elevated in numerous types of tumors. Therefore, inhibition of this enzyme provides an attractive target for the discovery of novel anticancer drugs. We performed virtual screening using a computer model derived from the X-ray crystal structure of human AdoMetDC and the National Cancer Institute's Diversity Set (1990 compounds). Our docking study suggested several compounds that could serve as drug candidates since their docking modes and scores revealed potential inhibitory activity toward AdoMetDC. Experimental testing of the top-scoring compounds indicated that one of these compounds (NSC 354961) possesses an IC50 in the low micromolar range. A search of the entire NCI compound collection for compounds similar to NSC 354961 yielded two additional compounds that exhibited activity in the experimental assay but with significantly diminished potency relative to NSC 354961. In this report, we disclose the activity of NSC 354961 against AdoMetDC and its probable binding mode based on computational modeling. We also discuss the importance of virtual screening in the context of enzymes that are not readily amenable to high-throughput assays, thereby demonstrating the efficacy of virtual screening, combined with selective experimental testing, in identifying new potential drug candidates.
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PMID:In silico chemical library screening and experimental validation of a novel 9-aminoacridine based lead-inhibitor of human S-adenosylmethionine decarboxylase. 1767 32