Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inosine 5 -monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme for the synthesis of GTP and dGTP. Two isoforms of IMPDH have been identified. IMPDH Type I is ubiquitous and predominantly present in normal cells, whereas IMPDH Type II is predominant in malignant cells. IMPDH plays an important role in the expression of cellular genes, such as p53, c-myc and Ki-ras. IMPDH activity is transformation and progression linked in cancer cells. IMPDH inhibitors, tiazofurin, selenazofurin, and benzamide riboside share similar mechanism of action and are metabolized to their respective NAD analogues to exert antitumor activity. Tiazofurin exhibits clinical responses in patients with acute myeloid leukemia and chronic myeloid leukemia in blast crisis. These responses relate to the level of the NAD analogue formed in the leukemic cells. Resistance to tiazofurin and related IMPDH inhibitors relate mainly to a decrease in NMN adenylyltransferase activity. IMPDH inhbitors induce apoptosis. IMPDH inhitors are valuable probes for examining biochemical functions of GTP as they selectively reduce guanylate concentration. Incomplete depletion of cellular GTP level seems to down-regulate G-protein function, thereby inhibit cell growth or induce apoptosis. Inosine 5'-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) catalyzes the dehydrogenation of IMP to XMP utilizing NAD as the proton acceptor. Studies have demonstrated that IMPDH is a rate-limiting step in the de novo synthesis of guanylates, including GTP and dGTP. The importance of IMPDH is central because dGTP is required for the DNA synthesis and GTP plays a major role not only for the cellular activity but also for cellular regulation. Two isoforms of IMPDH have been demonstrated. IMPDH Type I is ubiquitous and predominately present in normal cells, whereas the IMPDH Type II enzyme is predominant in malignant cells. Although guanylates could be salvaged from guanine by the enzyme hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8), the level of circulating guanine is low in dividing cells and this route is probably insufficient to satisfy the needs of guanylates in the cells.
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PMID:Consequences of IMP dehydrogenase inhibition, and its relationship to cancer and apoptosis. 1039 Jun 1

Inosine 5'-monophosphate dehydrogenase (IMPDH) represents an attractive target for the development of anticancer agents; however, there are no drugs aimed at this target for the treatment of cancer currently available on the market. Tiazofurin, a potent IMPDH inhibitor, reached clinical trials with Orphan Drug status for the treatment of patients in blast crisis of chronic myelogenous leukemia (CML); however, it was considered too toxic for application against other malignancies and no development has been reported for this drug since 2002. Formulations of mycophenolic acid, another potent inhibitor of IMPDH, are currently used for the prevention of rejection following transplantation, and against autoimmune diseases. More recently, numerous studies have demonstrated the potential of mycophenolic acid as an anticancer agent, with a phase I clinical trial in patients with advanced multiple myeloma ongoing. Furthermore, synergy between imantinib and mycophenolic acid in CML treatments has also been reported. Related compounds such as mycophenolic adenine dinucleotides, along with second-generation analogs, are undergoing preclinical evaluation, while another inhibitor of IMPDH, AVN-944, is currently in phase I clinical trials to investigate the treatment of hematological malignancies. This article reviews recent applications of IMPDH inhibitors as anticancer agents, and highlights the progress that has been made in this field.
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PMID:Recent development of IMP dehydrogenase inhibitors for the treatment of cancer. 1765 81