Disease relevance of Covidarabine

• Lengthy follow-up will be required to determine a median duration for the responses of hairy-cell leukemia to pentostatin [1].
• Its toxicity may be lower than that of deoxycoformycin, and the responses were achieved with single courses of treatment [2].
• Pentostatin in refractory chronic lymphocytic leukemia: a phase II trial of the European Organization for Research and Treatment of Cancer [3].
• Pentostatin in prolymphocytic leukemia: phase II trial of the European Organization for Research and Treatment of Cancer Leukemia Cooperative Study Group [4].
• Phase II investigation of pentostatin in multiple myeloma: a Southwest Oncology Group study [5].

Psychiatry related information on Covidarabine

• Deoxycoformycin (500 micrograms/kg IP), administered 15 min prior to ischemia, prevented the increase in locomotor activity normally observed with this model and significantly reduced the ischemia-induced damage to CA1 hippocampal neurons [6].
• In accordance, administration of deoxycoformycin increased REM and deep slow-wave sleep [7].

High impact information on Covidarabine

• Transfer and expression of the neomycin-resistance gene (neo) and the ADA gene in murine bone marrow colony-forming units (CFU) was demonstrated by in vitro colony formation in the presence of the antibiotic G418 or 9-xylofuranosyladenine plus deoxycoformycin, respectively [8].
• When grown in tissue culture medium supplemented with horse serum these cells provide a deaminase-free system not requiring the use of an adenosine deaminase inhibitor [9].
• We have established the DU.528 cell line from the pretreatment leukemia cells of a patient who underwent a T lymphoblastic-to-promyelocytic phenotype conversion during treatment with the adenosine deaminase inhibitor, deoxycoformycin [10].
• C57BL/6 fetal thymuses treated with the specific ADA inhibitor 2'-deoxycoformycin exhibited features of the human disease, including accumulation of dATP and inhibition of S-adenosylhomocysteine hydrolase enzyme activity [11].
• The effect of EHNA was not a result of adenosine deaminase inhibition, since 2'-deoxycoformycin (1-30 microM), another adenosine deaminase inhibitor with no effect on PDE2, or adenosine (1-10 microM) did not increase ICa [12].

Chemical compound and disease context of Covidarabine

• Deoxyadenosine has been implicated as the toxic metabolite causing profound lymphopenia in immunodeficient children with a genetic deficiency of adenosine deaminase (ADA), and in adults treated with the potent ADA inhibitor deoxycoformycin [13].
• OBJECTIVE: To determine whether clinical cross-resistance and intolerance exists between the nucleosides 2'-deoxycoformycin (DCF) and 2-chlorodeoxyadenosine (2-CdA) in the treatment of patients with hairy cell leukemia despite similar structures and mechanisms of action [14].
• Functional studies of murine hypoxia revealed inhibition of ADA with deoxycoformycin (dCF) enhances protective responses mediated by adenosine (vascular leak and neutrophil accumulation) [15].
• Building on the prior work of use of pentostatin in chronic lymphocytic leukemia (CLL), we initiated a trial of combined pentostatin (2 mg/m(2)), cyclophosphamide (600 mg/m(2)), and rituximab (375 mg/m(2)) for 65 symptomatic, previously untreated patients [16].
• In addition, case records from National Cancer Institute (NCI) Group C protocols were reviewed for fludarabine in chronic lymphocytic leukemia (CLL), and cladribine and pentostatin in hairy cell leukemia (HCL), as well as adverse drug reactions reported to the NCI from January 1980 through September 1993 [17].

Biological context of Covidarabine

• NH3 production derived only from the deamination of adenosine by the enzyme adenosine deaminase and was abolished by 0.4 microM 2'-deoxycoformycin, a specific inhibitor of adenosine deaminase [18].
• Kinetics of recovery of CD4+ T cells in peripheral blood of deoxycoformycin-treated patients [19].
• The involvement of adenosine receptors was suggested, because neither an adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride, nor an inhibitor of cellular nucleoside transport, dipyridamole, was able to inhibit adenosine-induced ASMC apoptosis [20].
• Clinical pharmacology of deoxycoformycin [21].
• Influx kinetics were the same in L1210 cells, in adenosine triphosphate-depleted L1210 cells (L1210/ara-C/MMPR) which have substantially reduced ability for [3H]adenosine phosphorylation, and in the presence of 2'-deoxycoformycin, a potent inhibitor of adenosine deaminase [22].

Anatomical context of Covidarabine

• Exposing lymphocytes to deoxycoformycin and deoxyadenosine was found to induce biochemical and physical effects similar to those of photochemotherapy [23].
• Pentostatin was used to treat 26 patients with advanced B-cell chronic lymphocytic leukemia resistant to conventional treatment [3].
• Cerebrospinal fluid levels of 2'-deoxycoformycin after systemic administration in monkeys [24].
• Monocytes exposed in vitro to CldAdo, or to dAdo plus deoxycoformycin rapidly developed DNA strand breaks [25].
• These observations show that malignant thymocytes are dependent on adenosine-deaminase activity and suggest that it may be possible to use deoxycoformycin in other patients with Thy-ALL to induce remission or to kill Thy-ALL blasts in bone marrow harvested before autologous bone-marrow transplantation, leaving normal haemopoietic stem cells intact [26].

Associations of Covidarabine with other chemical compounds

• To test this hypothesis, we measured methionine synthesis by the use of [14C]formate as a radioactive precursor in cultured human T and B lymphoblasts treated with varying concentrations of purine nucleosides; 2'-deoxycoformycin and 8-aminoguanosine were added to inhibit adenosine deaminase and purine nucleoside phosphorylase, respectively [27].
• Remission induction with adenosine-deaminase inhibitor 2'-deoxycoformycin in Thy-lymphoblastic leukaemia [26].
• Of 18 nonresponders, 9 pts subsequently received other treatments; 5 pts were retreated with cladribine, 3 underwent splenectomy, and 1 received pentostatin [28].
• With the exception of a transient increase in peripheral blood T cells during treatment with deoxycoformycin (DCF), the MNCs remained essentially constant throughout therapy with no evidence of a co-existing T-cell clone to account for the TCR beta rearrangement [29].
• Clinical pharmacology of 9-beta-D-arabinofuranosyladenine in combination with 2'-deoxycoformycin [30].

Gene context of Covidarabine

• Effect of deoxycoformycin and Val-boroPro on the associated catalytic activities of lymphocyte CD26 and ecto-adenosine deaminase [31].
• The importance of this reaction in the female reproductive tract of mice is suggested by pronounced utero-placental expression of ADA, and by embryolethality of the potent ADA-inhibitor deoxycoformycin (dCF) on day 7-8 of gestation [32].
• Inhibition of endogenous adenosine deaminase activity by erythro-9-(2-hydroxy-3-nonyl)adenine or 2'-deoxycoformycin strongly enhanced the inhibitory effects of exogenous adenosine on cytokine release and expression of E-selectin and VCAM-1 [33].
• The sera of 26 patients with hairy cell leukemia were examined for the presence of a soluble IL-2 receptor before and during therapy with either recombinant interferon alpha-2a or 2'-deoxycoformycin [34].
• Circulating levels of interleukin-6, tumor necrosis factor-alpha, and soluble tumor necrosis factor type II receptor were decreased in septic mice treated with pentostatin [35].

Analytical, diagnostic and therapeutic context of Covidarabine

• Whether pentostatin is superior to splenectomy or interferon as therapy for hairy-cell leukemia will have to be assessed by direct comparison in randomized studies [1].
• Efficacy of 2'-deoxycoformycin in hairy-cell leukemia: a study of the National Cancer Institute of Canada Clinical Trials Group [36].
• Thus, pentostatin is active, even in patients with advanced B-cell chronic lymphocytic leukemia that is refractory to multiple chemotherapy regimens [3].
• The role of ATP depletion and release of purines in myocardial injury was assessed using the selective nucleoside transport blocker p-nitrobenzylthioinosine (NBMPR) in a combination with specific adenosine deaminase inhibitor erythro-9-[hydroxy-3-nonyl]adenine (EHNA) administered during reperfusion after reversible ischemic injury [37].
• An in vivo murine model for immunodeficiency of both B and T cells is produced by continuous intraperitoneal infusion of 2'-deoxycoformycin (DCF), a specific tightly binding inhibitor of adenosine deaminase (ADase; adenosine aminohydrolase, EC 3.5.4.4) [38].

References