Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
 11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple endocrine neoplasia type 1 (MEN1) is tightly linked to the muscle-type glycogen phosphorylase (PYGM) gene in 11q13. This region of the human genome contains additional disease-related loci implicated in the development of insulin-dependent diabetes mellitus, familial paraganglioma type 2, spinocerebellar ataxia type 5, Bardet-Biedl syndrome and translocation t(11;17) described in B-cell non-Hodgkin's lymphoma. We approached cloning of candidate disease genes from 11q13 by large-scale genomic sequencing. We obtained > 106 kb of sequence around the PYGM gene and established a transcriptional map that includes: (i) two genes previously localized to 11q13, PYGM and a zinc-finger protein (ZFM1) gene; (ii) the germinal center kinase (GCK, human B-lymphocyte serine/threonine protein kinase) gene; (iii) a novel human CDC25-like (HCDC25L) gene; (iv) a dystrophia myotonica protein kinase-like (DMPKL) gene; and (v) a novel ubiquitously expressed gene of unknown function (germinal center kinase- neighboring gene, GCKNG).
 ...
PMID:The germinal center kinase gene and a novel CDC25-like gene are located in the vicinity of the PYGM gene on 11q13. 934 81

This review focuses on the clinical development of the prototype broad spectrum inhibitor of cyclin-dependent kinases (CDKs), flavopiridol, now undergoing Phase II single-agent trials and Phase I combination trials (with paclitaxel and cisplatin). Preclinically, flavopiridol is a potent inhibitor of CDKs 1, 2 and 4 in cell-free assays (IC(50)in the region of 100 nM) and tumour cell growth in vitro (typical IC(50)in the region of 100 nM). The drug showed in vivo antitumour activity (using iv., ip. or oral dosing) against a variety of human tumour xenografts, especially when administered on a regular daily, rather than weekly, schedule and most notably against prostate carcinoma, head and neck cancer, non-Hodgkin's lymphoma and leukaemia. The major toxicities observed in rodents were on the bone marrow and gastrointestinal tract. Pharmacokinetics were linear with dose and with a bi-exponential decline both in rodents and man. Oral bioavailability in rodents is in the region of 20%. Glucuronidation appears to be the major route of metabolism. Single-agent clinical trials have mainly used a 72 h continuous infusion schedule. Dose-limiting toxicities were diarrhoea and hypotension. Plasma concentrations in excess of those required for in vitro enzyme or cell growth inhibition are achievable. While there has been some evidence of single-agent antitumour activity (partial responses in a patient with renal cancer and another with gastric cancer), ongoing combination studies, especially with paclitaxel, where preclinical synergistic antitumour effects are observed, are promising. Doubt as to whether CDKs are the sole target responsible for the drug's antitumour effects have been raised by preclinical observations of apoptosis of non-cycling cells, effects on endothelial cells and non-CDK proteins, such as aldehyde dehydrogenase and glycogen phosphorylase, potent effects on PTEFb and transcription and its ability to directly interact with DNA.
 ...
PMID:Flavopiridol, the first cyclin-dependent kinase inhibitor to enter the clinic: current status. 1109 60