Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0854467 (myelosuppression)
 5,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Benzamide riboside (BR), a synthetic C-nucleoside, acts as a strong growth inhibitor of cancer cells in vitro and in vivo. BR, like TR and related nucleoside prodrugs, act by anabolism to NAD analogs. These analogs selectively inhibit IMPDH, leading to depletion of cellular GTP, growth cessation, and cell differentiation. To date only preclinical studies have been carried out. However, in tiazofurin (TR), a related drug, phase I/II clinical trials have been conducted in patients with acute leukemia and shown to be a very promising agent with a response rate of 85% in 26 patients in one of the trials. Tiazofurin is now undergoing phase III clinical trials as a result. Dose limiting toxicity of tiazofurin was headache, somnolence and nausea with no myelosuppression noted. By contrast, BR showed skeletal muscle toxicity, hepatotoxicity and myelosuppression in preclinical data. Skeletal muscle toxicity was noted in the paraspinal muscles and may represent dose-limiting toxicity. Since BR does exhibit myelosuppression, the most common chemotherapy-related side effect in humans, careful judgment is warranted should BR be included in multidrug regimens, although BR's potent cytotoxicity to tumor cells in preclinical models still makes it a promising drug.
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PMID:Toxicity and efficacy of benzamide riboside in cancer chemotherapy models. 1196 43

Ras mutation is observed in 20-30% of human malignancies. Ras proteins belong to the family of G-proteins, which are able to bind and hydrolyze guanosine triphosphate reversibly. They are responsible for signal transduction within cell. Ras undergoes several steps of posttranslational modification, but only farmesylation is necessary for its biologic activity. The crucial enzyme of farnesylation - farnesyltransferase (FT-ase) has become a major target for the development of new anticancer agents--farnesyltransferase inhibitors (FTI). Mutation of Ras results in the abrogation of its normal GTP-ase activity and subsequently it causes a permanent activation of Ras with uncontrolled growth and proliferation of cells. Recently published trials revealed, that FTI are highly effective in several malignant disorders, including myeloid leukemias. FTI are bioavailable after oral administration and have an acceptable toxicity profile. No enhanced myelosuppression effect was noted. It was observed, that FTI may increase cytotoxic effect of some antineoplastic drugs and radiotherapy. It seems that these agents are an interesting and promising therapeutic option for patients, who were resistant to conventional chemotherapy. The benefits of ambulatory drug administration may improve the quality of life in oncological patients. The II phase trials with FTI are under way and we hope, that these agents will find an unquestionable position in treatment of patients with malignancies.
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PMID:[Ras signaling pathway as a target for farnesyltransferase inhibitors--a new, promising prospects in the treatment for malignant disorders]. 1576 63

Nelarabine is the prodrug of 9-beta-arabinofuranosylguanine (ara-G) and is therapeutically classified as a purine nucleoside analog. Nelarabine is converted to ara-G by adenosine deaminase and transported into cells by a nucleoside transporter. Ara-G is subsequently phosphorylated to ara-G triphosphate (ara-GTP), thereby initiating the therapeutic effect by inhibiting DNA synthesis. Nelarabine has been extensively studied in regards to its pharmacokinetics, and the data have demonstrated that ara-GTP preferentially accumulates in malignant T-cells. Clinical responses to nelarabine have been demonstrated in various T-cell malignancies and appear to correlate with a relatively high intracellular concentration of ara-GTP compared to nonresponders. Therefore, this unique drug feature of nelarabine accounts for clinical utilization in treating adult and pediatric patients with relapsed or refractory T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma. Neuropathy is the most predominant adverse effect associated with nelarabine and the incidence correlates with the dose administered. Myelosuppression has been observed, with thrombocytopenia and neutropenia as the most common hematologic complications. This article reviews the pharmacology, mechanism of action, and pharmacokinetic properties of nelarabine, as well as nelarabine's clinical efficacy in T-ALL, T-LBL, and other hematologic malignancies. The toxicity profile, dosage, and administration, and areas of ongoing and future research, are also presented.
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PMID:Profile of nelarabine: use in the treatment of T-cell acute lymphoblastic leukemia. 2061 9