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At least 163 records · Page 9Linked to original sources
PubMed1992

Rapid recovery from cytopenia in hairy cell leukemia after treatment with 2-chloro-2'-deoxyadenosine (CdA): relation to opportunistic infections.

Sixteen patients with symptomatic hairy cell leukemia were treated with a single course of 2-chloro-2'-deoxyadenosine (CdA), 0.7 mg/kg total dose. Twelve patients achieved complete remission (CR). One patient with a CD19+/CD5+/CD25- phenotype and one with a pentostatin-treated CD19+/CD25- variant form had minor responses. Two patients with advanced disease and poor performance status died early from invasive mycosis. Three patients recovered from infections caused by cytomegalovirus and by candida. No patient had infections caused by bacteria or by unknown organisms. The median time to full recovery from anemia and thrombocytopenia was 6 and 2 weeks from start of therapy, respectively. Patients with infections, however, recovered at 13 and 5 weeks, respectively. Neutrophil, monocyte, and lymphocyte counts returned to normal at a median of 5, 5, and 10 weeks, respectively. Infections developed more frequently in pancytopenic patients than in those with one or more blood cell count within the normal range (P less than .01). All patients with one or no previous therapy had a CR, whereas those with more than one previous regimen had a lower CR rate (P less than .01). Thus, 1 week of CdA therapy frequently induced CR also in patients resistant to interferon. Toxicity was limited, and recovery from cytopenia was faster than what is reported during interferon therapy.

2-Chloroadenosine↗
PubMed1992

[Alpha interferon treatment in hairy cell leukemia].

Since 1984 alpha-interferon (alpha IFN) has been the treatment of choice in cases of hairy-cell leukaemia. However, eight years' experience shows that, although a large majority of the patients are improved, they are not cured. Thus, a new type of cytostatic drug, perhaps capable of cure as well, may replace alpha-IFN for the treatment of hairy-cell leukaemia in the future.

2-Chloroadenosine↗
PubMed1992

The treatment of hairy cell leukemia: an update.

The treatment of hairy cell leukemia (HCL) requires continuing update. The role for splenectomy is extremely limited. Alfa-interferon therapy has been available and utilized for five years; there have been few complete remissions. The experience with Pentostatin has resulted in a majority of clinical complete remissions after several months of therapy, but persistence of a small percentage of hairy cells in the bone marrow. The most recent therapeutic agent, 2-chloro-deoxyadenosine (2-CDA) is given for seven days and results in a complete remission in the great majority of patients with no evidence of persistent bone marrow disease. If this trend persists, 2-CDA will become first line therapy for HCL as it may cure the disease.

2-Chloroadenosine↗
PubMed1992

2-Chlorodeoxyadenosine: an active agent in the treatment of cutaneous T-cell lymphoma.

Cutaneous T-cell lymphomas are disfiguring malignant lymphoproliferative disorders for which standard therapy has been principally palliative. 2-Chlorodeoxyadenosine (2-CdA), a new purine analogue resistant to degradation by adenosine deaminase that has substantial activity against lymphoid neoplasms, was administered to 16 patients with cutaneous involvement by T-cell lymphoma. All patients had failed topical treatment modalities and/or systemic therapies. Fifteen patients were evaluable; one patient was not evaluable due to incomplete therapy and follow-up. The overall response rate was 47%. Three of 15 patients (20%) achieved complete responses and four of 15 patients (27%) achieved partial responses. The median duration of response was 5 months. One patient remains in unmaintained complete remission at 52+ months. Therapy was well tolerated. Myelosuppression was the principal toxicity encountered, occurring in 8 of 15 (53%) patients. 2-CdA is an effective new agent for the treatment of cutaneous T-cell lymphoma and warrants further study both as a single agent and in combination regimens.

2-Chloroadenosine↗
PubMed1992

Current strategies for treatment of acute myeloid leukemia at St Jude Children's Research Hospital.

We examined the feasibility of maintaining specific plasma concentrations of ara-C and VP-16 in children with AML. Sixty-one children were treated with 6 sequential cycles of intensive chemotherapy consisting of: (1) cytarabine (ara-C)/VP-16, (2) ara-C/daunorubicin (Dauno), (3) VP-16/amsacrine (m-AMSA), (4) VP-16/5-azacytidine (5-Az), (5) ara-C/Dauno, and (6) ara-C/VP-16. Fifty-nine children had de novo AML, and 2 had a previous myelodysplastic syndrome. The number of patients with each specific FAB subtype was: M0-1; M1-7; M2-24; M3-7; M4-5; M5-11; and M7-6. Simultaneous continuous infusions of ara-C and VP-16 (cycle 1) given at individualized doses to achieve drug plasma concentrations of 1 microM and 30 microM, respectively, produced complete remission (CR) in 26 of 61 patients (43%); an additional 17 patients entered CR after Dauno/ara-C (cycle 2), and one patient required 4 cycles of chemotherapy to achieve CR (total CR rate = 72%). The preliminary 2-year event-free survival (EFS) for patients with FAB-M1 and -M2 AML was only 15% versus 40% for those with FAB-M4 and -M5 AML. Overall, 21 of the 61 patients remain in CR (2-yr EFS = 29%). We conclude that intense treatment with ara-C and VP-16 at doses individualized to achieve target plasma concentrations is feasible although severely myelosuppressive. It results in an acceptable CR rate, but does not improve EFS.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Chloroadenosine↗
PubMed1992

Effects of insulin and a tumour promoter, TPA, on glucose transport and metabolism in retinal pigmented epithelium in vitro.

We have studied the effects of insulin, adenosine and 12-O-tetradecanoylphorbol-13-acetate (TPA) on glucose metabolism of the retinal pigmented epithelial (RPE) cells in vitro. Insulin stimulates glucose transport, glucose oxidation and lipogenesis in RPE cells. TPA at low concentrations of insulin increases the rates of glucose transport and glucose oxidation. Depletion of adenosine in RPE cells by adenosine deaminase increases the rate of both glucose transport and 14CO2 formation and improves insulin-sensitivity of both processes. The effects of TPA on RPE cells cannot be explained by the activation of protein kinase C. An alternative possibility is that the effects of TPA on insulin-stimulated glucose disposal in RPE cells is mediated by a change in adenosine concentration and/or the affinity/number of its receptors.

2-Chloroadenosine↗
PubMed1992

Modulation of anti-Thy1 nephritis in the rat by adenine nucleotides. Evidence for an anti-inflammatory role for nucleotidases.

Extracellular adenine nucleotides are considered mediators of inflammation because they modulate functions of neutrophils and platelets. Until now, this role for adenine nucleotides has not been studied in vivo. In particular in the rat kidney, where ATP- and ADPase activity is present in the glomerular basement membrane, studies about the role of nucleotides may increase our understanding of the dynamics of glomerulonephritis (GN). Therefore, we examined effects of adenine derivatives ATP gamma S, ADP beta S and 2chloro-adenosine (2chloro-ADO) in vitro and during anti-Thy1 GN. The in vitro results show that ADP beta S and ATP gamma S are not degraded by glomerular nucleotidases but, on the other hand do stimulate O2- production of peritoneal exudate cells (PEC). In contrast, 2chloro-ADO significantly inhibits O2- production of peritoneal exudate cells. For in vivo studies rats were rendered nephritic by intravenous injection of monoclonal anti-Thy1 IgG (5 mg/kg body weight). Subsequently, rats were treated with saline (group 1, N = 10), 2chloro-ADO (group 2, N = 10), ADP beta S (group 3, N = 10) or ATP gamma S (group 4, N = 10). All analogs (10 mg/kg body weight) were administered both at t = 0 and t = 12 hour. After 24 hours, rats were sacrificed and kidneys were examined histochemically. In an additional group of nephritic rats (N = 5) proteinuria was studied after 2-chloro-ADO treatment. Results show increased intraglomerular platelet aggregation in nephritic rats treated with ADP beta S, whereas 2chloro-ADO inhibits aggregation significantly as compared with nephritic rats receiving saline. The percentage of granulocytes producing O2- is significantly increased in glomeruli after treatment of nephritic rats with ATP gamma S, whereas cell influx itself is not changed. In contrast, 2chloro-ADO inhibits intraglomerular O2- production, which is associated with the complete inhibition of proteinuria in the early phase of anti-Thy1 GN. These data demonstrate significant pro-inflammatory activities of extracellular adenine nucleotides during anti-Thy1 GN suggesting an anti-inflammatory role for glomerular ATP/ADPase, which in concert with 5' nucleotidase converts ATP and ADP to antiinflammatory ADO.

2-Chloroadenosine↗
PubMed1992

Growth inhibition of human glioma cells induced by 8-chloroadenosine, an active metabolite of 8-chloro cyclic adenosine 3':5'-monophosphate.

8-Chloroadenosine 3':5'-monophosphate (8ClcAMP) inhibits the growth of human glioma cell lines at much lower concentrations than more commonly used cyclic AMP analogues, without inducing morphological differentiation. The mechanism by which 8ClcAMP exerts this effect is not fully understood. We examined whether the growth-inhibitory effect of this compound is due to an active metabolite, using a sulforhodamine protein stain assay to determine the proliferation rate of the WF human glioma cell line. 8-Chloroadenosine, one of the metabolites, inhibited the proliferation of WF human glioma cells more potently than 8ClcAMP. In the presence of adenosine deaminase, which converts 8-chloroadenosine into 8-chloroinosine, 8-chloroadenosine no longer inhibited human glioma cell growth. Addition of adenosine deaminase also largely reduced the growth-inhibitory effect of 8ClcAMP, but not of 8-(4-chlorophenylthio)cAMP. High performance liquid chromatography analysis revealed that at least part of the 8ClcAMP in the culture medium is converted into 8-chloroadenosine. We concluded that 8ClcAMP exerts its growth-inhibitory effect through its active metabolite 8-chloroadenosine. Adenylate cyclase assays showed that 8-chloroadenosine does not affect the intracellular cAMP production through adenosine A1 or A2 receptor activation, which makes it unlikely that 8-chloroadenosine inhibits glioma cell growth by increasing the intracellular cyclic AMP concentration.

2-Chloroadenosine↗
PubMed1991

New purine analogues for the treatment of chronic B-cell malignancies.

Adenosine deaminase (ADA), a purine salvage pathway enzyme, appears to play a key role in normal lymphocyte growth, development, and differentiation. Three new purine nucleoside analogues, deoxycoformycin, fludarabine, and 2-chlorodeoxyadenosine, affect the normal function of the purine salvage pathway by inhibiting ADA or by acting as analogs of the ADA substrates. These agents show significant activity in the treatment of chronic B-cell leukemias and low-grade lymphomas. The pharmacology, mechanism of action, and clinical usefulness of these agents are discussed.

2-Chloroadenosine↗
PubMed1991

On the pharmacokinetics of 2-chloro-2'-deoxyadenosine in humans.

The antitumoral effect of 2-chloro-2'-deoxyadenosine (CdA) in the treatment of lymphoproliferative diseases in general and of hairy cell leukemia in particular has recently been demonstrated. Detailed information on the pharmacokinetics of CdA, however, is lacking. The pharmacokinetics of CdA after 2- and 24-h infusions of 0.14 mg/kg was described in 12 patients with lymphoproliferative diseases using a newly developed high-performance liquid chromatography method. The plasma concentration data from individual patients were fitted to a two-compartment model with alpha- and beta-half-lives of 35 +/- 12 (mean +/- SD) min and 6.7 +/- 2.5 h, respectively. The volume of distribution was 9.2 +/- 5.4 liters/kg. The steady-state concentration of CdA during the 24-h infusion was 22.5 +/- 11.1 nM. The areas under the time versus concentration curves were 552 +/- 258 and 588 +/- 185 nM x h, respectively, for the 24- and 2-h infusions. The interindividual variability of the determinants of the plasma pharmacokinetics of CdA was small (the coefficients of variation were between 0.22 and 0.58). At 6.3 +/- 1.5 h after the start of the 2-h infusion, the concentration of CdA was the same as the steady-state concentration during the 24-h infusion. When the mean plasma concentrations of the 12 patients were fitted to a 3-compartment model, the half-lives of the alpha-, beta-, and tau-phases were 8 min, 1 h 6 min, and 6.3 h, respectively. The long terminal half-life of CdA after 2-h infusion supports the use of intermittent infusions.

2-Chloroadenosine↗
PubMed1991

Inhibitory effect of 2-chlorodeoxyadenosine on granulocytic, erythroid, and T-lymphocytic colony growth.

Previous studies have shown that 2-chloro-2'-deoxyadenosine (CdA) is markedly toxic to normal and malignant human lymphocytes in vitro and in vivo. Recent clinical trials have shown that CdA is a very promising drug for the treatment of lymphoid malignancies. The present investigations were designed to test the effect of CdA on the in vitro clonal growth of both myeloid progenitors and T-lymphocyte colony-forming cells (CFU-TL) obtained from normal human bone marrow and peripheral blood. Cells were exposed to CdA in doses up to 1280 nmol/L. To reduce indirect effects of CdA mediated by accessory cells, monocyte- and T-lymphocyte-depleted bone marrow cells were used for our investigations. The results show a marked inhibition of myeloid progenitor and lymphocyte colony-forming cells in a dose-dependent manner, correlating with maturation stage in that the immature progenitor cells are more sensitive to this drug. Furthermore, our studies suggest that a sequence of metabolic events previously described for lymphocytes may be operative in myeloid progenitor cells because a minimal exposure time of 48 hours is required to obtain a marked inhibition. CdA toxicity was proposed to be linked with phosphorylation by deoxycytidine-kinase (E.C. 2.7.1.74), the levels of which have been found to be high in lymphocytes, but low in granulocytes. However, the marked inhibition of myeloid progenitor cells shown in these studies suggests that other factors such as modulation of the effect of CdA by the ambient levels of other deoxynucleosides might influence the apparent sensitivity of myeloid cells.

2-Chloroadenosine↗
PubMed1990

gamma-Aminobutyric acidA receptor regulation in culture: altered allosteric interactions following prolonged exposure to benzodiazepines, barbiturates, and methylxanthines.

In previous reports, we have described the use of primary neuronal cultures derived from chick brain to study the regulation of the gamma-aminobutyric acidA (GABAA) receptor complex. Chronic exposure of cultures to GABA, benzodiazepines, or methylxanthines results in decreased enhancement of [3H]flunitrazepam binding by GABA, consistent with an allosteric uncoupling of GABA and benzodiazepine recognition sites of the GABAA receptor. In the present communication, we extend our studies of the pharmacology of benzodiazepine- and methylxanthine-induced uncoupling of GABA/benzodiazepine recognition site interactions and present evidence to show that certain barbiturates (barbital and pentobarbital) also induce uncoupling. Chronic exposure to flurazepam (a high efficacy benzodiazepine) elicits no change in the number of benzodiazepine binding sites or the affinity of benzodiazepine binding in the absence of GABA. Whereas flurazepam and theophylline decrease coupling, Ro15-1788 (a low efficacy benzodiazepine) inhibits flurazepam-induced but not theophylline-induced uncoupling, suggesting that theophylline and flurazepam act through separate receptors. Flurazepam-induced uncoupling is not prevented by SR-95531 or picrotoxin (specific inhibitors of GABA action) and, therefore, is not an indirect effect mediated by endogenous GABA. The onset of flurazepam-induced uncoupling (EC50 approximately 1 microM) exhibits a t 1/2 of about 18 hr, in general agreement with the half-time for receptor turnover. Uncoupling is reversible following washout and recovery at 37 degrees. These results are discussed in terms of mechanisms of GABAA receptor regulation in response to chronic exposure to functionally homologous or heterologous ligands.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Dependence of cell survival on DNA repair in human mononuclear phagocytes.

Mononuclear phagocytes play a central role in the pathogenesis of chronic inflammatory diseases. It is therefore important to define chemotherapeutically exploitable metabolic pathways that distinguish monocytes from other cell types. Blood monocytes do not synthesize deoxynucleotides de novo, and their transformation to macrophages occurs without cell division. Whether or not monocytes can repair DNA damage, and whether or not DNA repair is necessary for their survival, is unknown. The present experiments demonstrate that normal human monocytes, unlike neutrophils, rapidly repair DNA strand breaks induced by gamma-irradiation. Monocyte extracts contain functional immunoreactive DNA polymerase-alpha. DNA repair synthesis in normal monocytes is blocked by aphidicolin, an inhibitor of DNA polymerase-alpha with respect to dCTP. Aphidicolin is also directly toxic to normal monocytes, but has no effect on nondividing lymphocytes or fibroblasts. Compared to most other cell types, monocytes and macrophages have very low dCTP pools, but abundant deoxycytidine kinase activity. This suggests that dCTP derived from salvage pathways is important for DNA repair in these cells. Consistent with this notion, exogenous deoxycytidine could partially protect monocytes from aphidicolin killing. The unexpected toxicity of aphidicolin toward normal human monocytes may be attributable to their high rate of spontaneous DNA strand break formation, to the importance of DNA polymerase-alpha for DNA repair in these cells, and to their minute dCTP pools.

2-Chloroadenosine↗