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)

The studies on the metabolism and toxic mechanism of 2-chloro-2'-deoxyadenosine (2CdA, Cladribine), a new antileukemic drug, were reviewed. 2CdA, being a 2-halogenated, adenosine deaminase-resistant analogue of deoxyadenosine, is phosphorylated to the mono-, di, and triphosphate chlorodeoxy adenosine and the first step of phosphorylation is taken in the presence of enzymes, mainly kinase deoxycytidine (although in mitochondria it is phosphorylated by kinase deoxyguanosine). Triphosphate derivative of 2CdA is commonly considered to be the agent inducing cell apoptosis resulting from inhibition of ribonucleotide reductase, DNA polymerases and DNA repair. Recent studies on toxicity of 2CdA showed that the nucleoside possesses inhibitory activity against enzymes which are responsible for metabolism of deoxyadenosine, which suggests that the mechanism of toxicity by 2CdA includes a block in dAdo metabolic pathways which is very important for normal function of immune system cells. The agent under discussion and two other adenosine analogues (i.e. fludarabine and 2'-deoxycoformycin) which exhibit cytotoxicity against dividing and resting lymphocytes revolutionized the treatment of indolent lymphoid malignancies (i.e. chronic lymphocytic leukemia, non-Hodgkin's lymphoma, cutaneous T cell lymphoma and hairy cell leukemia). Particularly, in the treatment of hairy cell leukemia, 2-chloro-2'-deoxyadenosine demonstrated excellent efficacy, achieved after a single 7-day course, with an acceptable tolerability profile, suggesting that cladribine is likely to be more effective than other agents recommended in this disease. Preliminary clinical data, extremely encouraging in the case of 2CdA indicate that biomolecular mechanisms of the drug cytotoxicity is worth wide presentation.
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PMID:2-Chloro-2'-deoxyadenosine (2CdA) biochemical aspects of antileukemic efficacy. 941 93

The purpose of this study was to analyse the proliferative fraction with the monoclonal antibody M1-R-R to M1-subunit ribonucleotide reductase and with MIB-1 to Ki-67 antigen in relation to p53 protein expression in fine needle aspirates from B-cell non-Hodgkin's lymphomas. One hundred and thirty-seven cases, previously diagnosed and sub-typed according to the Kiel classification and characterized by immunophenotyping, were included in the study. The M-1 subunit ribonucleotide reductase (M1-R-R), Ki-67 and p53 antigens were detected using monoclonal antibodies on stored cytospin preparations. There was a good correlation (r = 0.72) between Ki-67 and M1-R-R positive cell fraction in both high and low grade lymphomas. High-grade lymphomas had a median percentage of M1-R-R/MIB-1 positive cells of 53.0/73.0 for lymphoblastic, 61.0/52.0 for immunoblastic and 33.5/41.0 for centroblastic lymphomas, respectively. In low grade lymphomas figures of median percentage of M1-R-R/MIB-1 were 9.0/15.0 for centroblastic/centrocytic, 11.0/9.5 for chronic lymphocytic leukaemia, 16.0/27.0 for centrocytic and 12.0/9.0 for immunocytomas, respectively. The median percentages of M1-R-R/MIB-1 for high and low grade lymphomas were 37.0/50.5 and 11.0/12.0, respectively. In the p53 positive cases the proliferation rate as measured by staining for M1-R-R and MIB-1 was higher than in p53 negative cases, but the difference was not statistically significant. The results show that cytospin material obtained by fine needle aspiration and stored at -70 degrees C for years can be used reliably for both peroxidase-avidin-biotin and three-step alkaline phosphatase immunocytochemical staining. In addition, proliferation fraction determined by M1-R-R monoclonal antibody staining correlates well with that measured by an established marker for cell proliferation, the Ki-67 antibody. However, the proliferation fraction as measured by the two antibodies differs in the various subtypes of non-Hodgkin's lymphoma which indicates that they may contribute different prognostic information.
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PMID:Analysis of proliferating cell fraction determined by monoclonal antibody to M1-subunit ribonucleotide reductase and Ki-67 in relation to p53 protein expression in fine-needle aspirates from non-Hodgkin's lymphomas. 1101 56

Gallium nitrate is effective and well tolerated for the treatment of cancer-related hypercalcemia. At somewhat higher doses, gallium nitrate also has cytotoxic activity against a variety of cancers. The probable mechanism is inhibition of both ribonucleotide reductase and a protein tyrosine phosphatase. Radioactive gallium ((67)Ga) is concentrated at sites of malignant lymphoma, Hodgkin's disease, and other tumors. Gallium nitrate has substantial single-agent activity in the treatment of patients with advanced lymphoma and has also shown activity when used in combination with other agents. Significant response rates have been observed in patients with diffuse large cell lymphoma, small lymphocytic lymphoma, and follicular lymphoma. Because of its unique mechanism of action, gallium nitrate could be non-cross-resistant with many of the cytotoxic agents used as standard chemotherapy for non-Hodgkin's lymphoma. Nephrotoxicity, the most frequent adverse event associated with gallium nitrate, can generally be minimized by ensuring adequate oral hydration and avoiding concomitant use of other nephrotoxic drugs. Gallium nitrate causes little myelosuppression and is therefore well tolerated by patients with advanced disease who have received extensive prior therapy. Given its unique mechanism of action, the high level of single-agent activity in published clinical trials, the absence of significant myelosuppression, and the potential lack of cross-resistance, further clinical study of gallium nitrate both alone and in combination with other active agents is warranted.
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PMID:Gallium nitrate in the treatment of lymphoma. 1277 57

Antisense oligonucleotides (ASONs) are one of the new classes of molecularly targeted agents that have transitioned from the laboratory into clinical trials. Rational drug design has resulted in agents directed against a number of important cellular targets, including the mRNA of bcl-2, protein kinase (PK) C-alpha, PKA-I, H-ras, c-raf, R1 and R2 subunit of ribonucleotide reductase, and transforming growth factor beta2. These drugs are well tolerated with favorable toxicity profiles, and preliminary studies have demonstrated that they can be feasibly combined with chemotherapy. Plasma half-life is short, generally necessitating continuous prolonged intravenous infusion. Shorter administration schedules are being investigated. Efficacy has been demonstrated in early-phase studies in non-small-cell lung cancer (NSCLC), non-Hodgkin's lymphoma, ovarian cancer, melanoma, and prostate cancer. Molecular correlative studies with peripheral blood mononuclear cells and tumor tissue have demonstrated suppression of target proteins, suggesting that these drugs are indeed reaching the target. Here we discuss the current status of development of ASONs, focusing on LY900003 (formerly ISIS 3521), an agent directed against PKC-alpha currently under study in NSCLC. Phase III studies will determine the ultimate role these agents will play in the treatment of cancer. Future areas of study include combination with radiation and other molecularly targeted agents, alternative dosing schedules, liposomal administration, and the development of new antisense agents directed against additional molecular targets.
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PMID:Antisense oligonucleotides in the treatment of non-small-cell lung cancer. 1472 Mar 40

Mortality from non-Hodgkin's lymphoma (NHL) is high, thus defining the need for additional therapeutic agents for this disease. Gallium nitrate is a metal compound that is presently approved for the treatment of hypercalcaemia associated with malignancy. In clinical trials first conducted over two decades ago, this drug was found to have antineoplastic activity in NHL. However, its development as an antineoplastic agent for the treatment of NHL was never rigorously pursued. Gallium has unique mechanisms of action that include its binding to transferrin in the circulation and targeting transferrin receptors present on lymphoma cells. As it shares chemical properties with iron, gallium can disrupt critical steps in iron homeostasis that are essential for tumour cell viability and growth and can inhibit the iron-dependent activity of ribonucleotide reductase. The drug may also target other cellular processes unrelated to iron. Phase I/II studies have shown that gallium nitrate displays the most efficacy and lowest toxicity in NHL when administered as a continuous intravenous infusion, producing response rates of 43% in patients with relapsed or refractory NHL. It does not suppress the white blood cells or platelets and does not share cross-resistance with other chemotherapeutic drugs. These characteristics make it particularly attractive for the treatment of myelosuppressed patients and for incorporation into combination therapy. Multi-institutional Phase II clinical trials are in progress to evaluate gallium nitrate as a single agent or in combination. These studies will help define its role in the current treatment of NHL.
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PMID:Gallium nitrate for the treatment of non-Hodgkin's lymphoma. 1515 28

The trivalent gallium cation is capable of inhibiting tumor growth, mainly because of its resemblance to ferric iron. It affects cellular acquisition of iron by binding to transferrin, and it interacts with the iron-dependent enzyme ribonucleotide reductase, resulting in reduced dNTP pools and inhibition of DNA synthesis. The abundance of transferrin receptors and the up-regulation of ribonucleotide reductase render tumor cells susceptible to the cytotoxicity of gallium. Remarkable clinical activity in lymphomas and bladder cancer has been documented in clinical studies employing intravenous gallium nitrate, which is currently being re-evaluated in non-Hodgkin's lymphoma. An improved therapeutic index is expected to result from prolonged exposure to low steady-state plasma gallium levels. Attempts to accomplish this by oral administration of gallium chloride failed because of insufficient intestinal absorption. Complexation of gallium with ligands, which stabilize gallium against hydrolysis and facilitate membrane permeation, has been recognized as a promising strategy for overcoming these limitations. Two such gallium complexes, namely tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III) (gallium maltolate) and tris(8-quinolinolato)gallium(III) (KP46), which both exhibit high bioavailability when administered via the oral route, are currently being evaluated in the clinical setting.
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PMID:Gallium in cancer treatment. 1557 97

Gallium nitrate inhibits the growth of various lymphoma cell lines in vitro and exhibits antitumor activity in patients with lymphoma. The mechanism(s) of cytotoxicity is (are) only partly understood but appears to involve a two-step process: (1) targeting of gallium to cells, and (2) acting on multiple, specific intracellular processes. Gallium shares certain chemical properties with iron; therefore, it binds avidly to the iron transport protein transferrin. Transferrin-gallium complexes preferentially target cells that express transferrin receptors on their surface. Expression of transferrin receptors is particularly high on lymphoma cells. Cellular uptake of the gallium-transferrin complex leads to inhibition of cellular proliferation primarily via disruption of iron transport and homeostasis and blockade of ribonucleotide reductase. Recent studies have shown that cellular uptake of gallium leads to activation of caspases and induction of apoptosis. In phase II trials in patients with relapsed or refractory lymphoma, the antitumor activity of gallium nitrate is similar to, or better than, that of other commonly used chemotherapeutic agents. Gallium nitrate is not myelosuppressive and may be used in patients with neutropenia or thrombocytopenia. A multicenter trial to evaluate the use of gallium nitrate in patients with relapsed non-Hodgkin's lymphoma is currently ongoing.
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PMID:Apoptotic mechanisms of gallium nitrate: basic and clinical investigations. 1565 Nov 76

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

Clinical trials have shown gallium nitrate, a group 13 (formerly IIIa) metal salt, to have antineoplastic activity against non-Hodgkin's lymphoma and urothelial cancers. Interest in gallium as a metal with anticancer properties emerged when it was discovered that 67Ga(III) citrate injected in tumor-bearing animals localized to sites of tumor. Animal studies showed non-radioactive gallium nitrate to inhibit the growth of implanted solid tumors. Following further evaluation of its efficacy and toxicity in animals, gallium nitrate, Ga(NO3)3, was designated an investigational drug by the National Cancer Institute (USA) and advanced to Phase 1 and 2 clinical trials. Gallium(III) shares certain chemical characteristics with iron(III) which enable it to interact with iron-binding proteins and disrupt iron-dependent tumor cell growth. Gallium's mechanisms of action include the inhibition of cellular iron uptake and disruption of intracellular iron homeostasis, these effects result in inhibition of ribonucleotide reductase and mitochondrial function, and changes in the expression in proteins of iron transport and storage. Whereas the growth-inhibitory effects of gallium become apparent after 24 to 48 hours of incubation of cells, an increase in intracellular reactive oxygen species (ROS) is seen with 1 to 4 hours of incubation. Gallium-induced ROS consequently triggers the upregulation of metallothionein and hemoxygenase-1 genes. Beyond the first generation of gallium salts such as gallium nitrate and gallium chloride, a new generation of gallium-ligand complexes such as tris(8-quinolinolato)gallium(III) (KP46) and gallium maltolate has emerged. These agents are being evaluated in the clinic while other ligands for gallium are in preclinical development. These newer agents appear to possess greater antitumor efficacy and a broader spectrum of antineoplastic activity than the earlier generation of gallium compounds.
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PMID:Gallium Complexes as Anticancer Drugs. 2939 29