Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Temozolomide (SCH 52365) is an imidazotetrazine derivative which exhibits broad spectrum activity against murine tumors and is structurally related to dacarbazine (DTIC). Temozolomide cytotoxicity is schedule dependent in vivo with a daily x 5 schedule showing the highest activity. Oral temozolomide is rapidly and completely absorbed with minimal interpatient and intrapatient variability in pharmacokinetics. Clinical studies have demonstrated activity against melanoma and glioma. The present study examined the activity of oral temozolomide against patients with pancreatic cancer. Patients with advanced pancreatic adenocarcinoma previously untreated with chemotherapy received temozolomide 200 mg/m2/day once daily orally for 5 days with cycles repeated every 28 days. There were 16 patients entered on study with 15 evaluable for response and toxicity. There were no responses seen in 15 evaluable patients with 14 manifesting progressive disease within 2 months of starting therapy. Toxicity was primarily hematological with 3 patients experiencing > or = grade 3 neutropenia and thrombocytopenia respectively. Other toxicities were relatively modest. In conclusion, temozolomide in the once daily x 5 schedule is inactive against adenocarcinoma of the pancreas.
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PMID:A phase II study of temozolomide in advanced untreated pancreatic cancer. 974 May 47

Ras oncogenes (K-, H- and N-ras) are known to be involved in signal transduction pathways regulating cell growth and differentiation in many human cancers. These proteins are synthesized as a cytosolic precursor that ultimately localizes to the inner plasma membrane. This process is initiated by the attachment of a farnesyl moiety to the protein and is catalysed by the farnesyl transferase. Since activated (mutated) ras oncogenes have been shown to be essential for the malignant phenotype in many tumors, farnesyl transferase inhibitors (FTIs) have emerged as a novel class of antineoplastic agents. Four FTIs are currently in clinical trials. Two of these agents, R-115777 and SCH-66336, are orally active heterocyclic compounds and already in phase II/III studies. Preliminary results of R-115777 or SCH-66336 in combination with gemcitabine or 5-FU/FA in patients with advanced pancreatic carcinomas have been reported. The dose-limiting toxicity was neutropenia, nausea, diarrhea and fatigue. The recommended doses for phase II studies were 200 mg R-115777 or 2 x 200 mg SCH-66336. Durable objective partial responses were noted in several patients. Furthermore, the FTIs were found to be well tolerated. Ongoing phase III studies in patients with advanced pancreatic cancers will determine the extent of clinical activity and whether these agents can be used as single agents for the treatment of pancreatic carcinomas or have to be used in combination with other cytostatic drugs. In addition, it remains to be clarified whether FTIs may sensitize drug-resistant cancers following conventional chemotherapy.
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PMID:Farnesyltransferase inhibitors--a novel approach in the treatment of advanced pancreatic carcinomas. 1282 Mar 5

Aurora kinase A, B and C, are key regulators of mitosis and are over expressed in many of the human cancers, making them an ideal drug target for cancer chemotherapy. Currently, over a dozen of Aurora kinase inhibitors are in various phases of clinical development. The majority of the inhibitors (VX-680/MK-0457, PHA-739358, CYC116, SNS-314, AMG 900, AT-9283, SCH- 1473759, ABT-348, PF-03814735, R-763/AS-703569, KW-2449 and TAK-901) are pan-selective (isoform non-selective) and few are Aurora A (MLN8054, MLN8237, VX-689/MK5108 and ENMD 2076) and Aurora B (AZD1152 and GSK1070916) sub-type selective. Despite the intensive research efforts in the past decade, no Aurora kinase inhibitor has reached the market. Recent evidence suggests that the sub-type selective Aurora kinase A inhibitor could possess advantages over pan-selective Aurora inhibitors, by avoiding Aurora B mediated neutropenia. However, sub-type selective Aurora kinase A inhibitor design is very challenging due to the similarity in the active site among the isoforms. Structural biology and computational aspects pertaining to the design of Aurora kinase inhibitors were analyzed and found that a possible means to develop sub-type selective inhibitor is by targeting Aurora A specific residues (Leu215, Thr217 and Arg220) or Aurora B specific residues (Arg159, Glu161 and Lys164), near the solvent exposed region of the protein. Particularly, a useful strategy for the design of sub-type selective Aurora A inhibitor could be by targeting Thr217 residue as in the case of MLN8054. Further preclinical and clinical studies with the sub-type selective Aurora inhibitors could help bring them to the market for the treatment of cancer.
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PMID:Structural Biology Insight for the Design of Sub-type Selective Aurora Kinase Inhibitors. 2589 1