Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diaziquone (AZQ), a new lipid-soluble antitumor agent, was given by 15-30-minute infusion on a daily X 5 schedule to 47 children with refractory solid tumors and leukemia. The starting daily dose of 6 mg/m2 was escalated to 10 and 35 mg/m2 in patients with solid tumors and leukemia, respectively. In patients with solid tumors, myelosuppression was dose-limiting at a daily dose of 10 mg/m2. In patients with leukemia, prolonged pancytopenia and bone marrow hypoplasia were observed at daily doses greater than or equal to 25 mg/m2. At these higher doses, significant hyperbilirubinemia associated with sepsis was also seen. Corresponding increases of transaminases or alkaline phosphatase and significant hemolysis were not noted. The maximum tolerated dose for this daily dose schedule was 9 mg/m2 in children with solid tumors and 25 mg/m2 in children with relapsed leukemia. Responses to AZQ included stabilization of disease in osteosarcoma, neurofibrosarcoma, pinealoma, and ependymoma. A patient with juvenile chronic myelocytic leukemia in blast crisis converted back to the chronic phase. A patient with acute lymphoblastic leukemia had a substantial decrease in cerebrospinal fluid blast count. Bone marrow aplasia was achieved in children with acute lymphoblastic leukemia and acute nonlymphoblastic leukemia; however, remissions were not achieved. A phase II study of AZQ in children with refractory malignancies is now being performed by the Childrens Cancer Study Group.
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PMID:Phase I clinical evaluation of diaziquone in childhood cancer. 385 80

Nucleostemin (NS) is a nucleolar-nucleoplasmic shuttle protein that regulates cell proliferation, binds p53 and Mdm2, and is highly expressed in tumor cells. We have identified NS as a target of oxidative regulation in transformed hematopoietic cells. NS oligomerization occurs in HL-60 leukemic cells and Raji B lymphoblasts that express high levels of c-Myc and have high intrinsic levels of reactive oxygen species (ROS); reducing agents dissociate NS into monomers and dimers. Exposure of U2OS osteosarcoma cells with low levels of intrinsic ROS to hydrogen peroxide (H(2)O(2)) induces thiol-reversible disulfide bond-mediated oligomerization of NS. Increased exposure to H(2)O(2) impairs NS degradation, immobilizes the protein within the nucleolus, and results in detergent-insoluble NS. The regulation of NS by ROS was validated in a murine lymphoma tumor model in which c-Myc is overexpressed and in CD34+ cells from patients with chronic myelogenous leukemia in blast crisis. In both instances, increased ROS levels were associated with markedly increased expression of NS protein and thiol-reversible oligomerization. Site-directed mutagenesis of critical cysteine-containing regions of nucleostemin altered both its intracellular localization and its stability. MG132, a potent proteasome inhibitor and activator of ROS, markedly decreased degradation and increased nucleolar retention of NS mutants, whereas N-acetyl-L-cysteine largely prevented the effects of MG132. These results indicate that NS is a highly redox-sensitive protein. Increased intracellular ROS levels, such as those that result from oncogenic transformation in hematopoietic malignancies, regulate the ability of NS to oligomerize, prevent its degradation, and may alter its ability to regulate cell proliferation.
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PMID:Reactive oxygen species regulate nucleostemin oligomerization and protein degradation. 2124 6