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

A phase II study of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate was done in non-Hodgkin's lymphoma with a loading dose/continuous intravenous infusion schedule, consisting of a 20 mg/m2 loading dose followed by a continuous i.v. infusion of 30 mg/m2/24 h for 48 h. The loading dose was held constant while the continuous i.v. dose was escalated or decreased as appropriate for toxicity. Twenty-six patients were entered on the study; 25 are evaluable for response. The patients' median age was 61 years (range 25 to 73); their mean performance status was 1.1. They had received a mean of 2.6 prior chemotherapeutic regimens, and six also had prior radiation therapy. There was one complete response lasting 9+ months, and there were seven partial responses lasting 20, 13, 11, 11, 10, 5, and 2 months (response rate 32%). Toxicity was acceptable and consisted mainly of myelosuppression. 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate is dephosphorylated in vivo and then is thought to be activated intracellularly to 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-triphosphate. The rate-limiting enzyme is deoxycytidine kinase. Deoxycytidine kinase activity was determined on pretreatment tumor samples for correlation with response. There was no difference between the values for responders and nonresponders. There was a trend for higher values in more malignant histological subtypes.
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PMID:Phase II trial of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate in non-Hodgkin's lymphoma: prospective comparison of response with deoxycytidine kinase activity. 243 57

Recently a few new purine nucleoside analogues (PNA) have been synthesized and introduced into preclinical and clinical trials. The transition-state theory has led to the design of 9-deazanucleotide analogues that are purine nucleoside phosphorylase (PNP) inhibitors, termed immucillins. Among them the most promising results have been obtained with forodesine. Forodesine (BCX-1777, Immucillin H, 1-(9-deazahypoxanthin)-1,4-dideoxy-1,4-imino-D-ribitol) has carbon-carbon linkage between a cyclic amine moiety that replaces ribose and 9-deaza-hypixanthine. The drug is a novel T-cell selective immunosuppressive agent which in the presence of 2'-deoxyguanosine (dGuo) inhibits human lymphocyte proliferation activated by various agents such as interleukin-2 (IL-2), mixed lymphocyte reaction and phytohemagglutinin. In the mechanism of forodesine action two enzymes are involved: PNP and deoxycytidine kinase (dCK). PNP catalyzes the phosphorolysis of dGuo to guanine (Gu) and 2'-deoxyribose-1-phosphate, whereas dCK converts dGuo to deoxyguanosino-5'-monophosphate (dGMP) and finally to deoxyguanosino-5'-triphosphate (dGTP). The affinity of dGuo is higher for PNP than for dCK. Nevertheless, if PNP is blocked by forodesine, plasma dGuo is not cleaved to Gu, but instead it is intracellularly converted to dGTP by high dCK activity, which leads to inhibition of ribonucleotide reductase (RR), an enzyme required for DNA synthesis and cell replication, which eventually results in apoptosis. Forodesine is active in some experimental tumors in mice, however it could be used for the treatment of human T-cell proliferative disorders and it is undergoing phase II clinical trials for the treatment of T-cell non-Hodgkin's lymphoma, which includes cutaneous T-cell lymphoma (CTCL). Moreover, recent preclinical and clinical data showed activity of forodesine in B-cell acute lympholastic leukemia (ALL).
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PMID:Forodesine (BCX-1777, Immucillin H)--a new purine nucleoside analogue: mechanism of action and potential clinical application. 1789 85