Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A limited number of biologically active materials were examined for their relative ability to selectively inhibit the replication of Gross or Rauscher murine leukemia virus (MLV) in Swiss mouse embryo cells by means of the UV-XC plaque-reduction assay. Among the compounds demonstrating significant antiviral activity against Gross MLV in vitro were 1-(4-fluorobenzyloxy) adenosine (FBAR), polyadenylic acid [poly(A)], the carbocyclic analogue of 6-methylthiopurine ribonucleoside (C-MeMPR), 3-(2,4-dinitrophenylhydrazonemethyl)rifamycin SV (AF/DNFI), and phosphonoacetic acid (PAA). Five compounds that exhibited significant antiviral activity against MLV in vitro were tested for similar activity against Rauscher MLV in vivo. Three of these selected compounds, pyrazofurin (pyrazomycin), ribavirin (Virazole), and 9-beta-D-arabinofuranosyladenine (ara-A), produced a significant (50%-100%) inhibition of virus-induced splenomegaly development in mice, whereas the other two candidate inhibitors, 3-deazauridine (deazaUR) and rifamycin SV, the other two candidate inhibitors, 3-deazauridine (deazaUR) and rifamycin SV, failed to demonstrate any in vivo activity in this 21-day leukemogenesis assay. The administration of an inhibitor of adenosine deaminase (Co-vidarabine) in combination with ara-A resulted in an enhanced antiviral response in both infected cell cultures and animals. Co-vidarabine also increased the potency of ara-AMP against Gross MLV in vitro, indicating the probable dephosphorylation of the compound to ara-A and its subsequent deamination to ara-H in this system.
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PMID:Selective inhibition of RNA tumor virus replication in vitro and evaluation of candidate antiviral agents in vivo. 28 Jan 46

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.
Leukemia 1992
PMID:The treatment of hairy cell leukemia: an update. 134 62

Deoxycoformycin (DCF) has been reported to cause immediate reduction and dysfunction of T lymphocytes, but the long-term effects on immune functions are still not known. As cytokine production is regulated by T helper-inducer lymphocytes and might represent a parameter for functional integrity of immunocompetent cells, we have measured the production of interleukin-2 (IL-2), tumor necrosis factor (TNF), and interferons (IFN) by peripheral mononuclear cells (PMNC) from 10 patients with hairy cell leukemia 11-24 months after end of therapy with DCF. The patients were in continuous remission at the time of study. Despite an absolute reduction in CD3+ and CD4+ lymphocytes. there were no significant differences in IL-2 or TNF release between patients and controls. Except for a significant reduction in IFN-alpha release stimulated by Newcastle disease virus (NDV), IFN productions induced by other mitogens (phytohemagglutinin, PHA; Concanavalin A, ConA; pokeweed mitogen, PWM) and viral antigens were within normal range. There was also a decrease in proliferative responsiveness to PHA, but responses to ConA, PWM, and other viral antigens were normal. In five of the patients, we have monitored closely the changes in IL-2, TNF, and IFN before, during, and after treatment and could demonstrate a rapid normalization of initially decreased IL-2 release in all cases and also of TNF if the initial production was reduced. This study shows that, even though the absolute number of T lymphocytes and helper cells are reduced in the long-term observation after DCF treatment, the capacity to produce IL-2, TNF, and IFN-gamma was within normal range. Parallel to this observation, no opportunistic infections or frequency of infectious complications occurred in these patients.
Leukemia 1990 Aug
PMID:Long-term effects of 2'-deoxycoformycin treatment on cytokine production in patients with hairy cell leukemia. 169 12

Hairy-cell leukemia is an unusual chronic lymphoid leukemia with distinctive clinical and pathological features. The management of this disorder has been revolutionized in the last decade with the discovery of the efficacy of alpha interferon and the inhibitors of adenosine metabolism, deoxycoformycin and chlorodeoxyadenosine. The best treatment protocol for hairy-cell leukemia has not yet been defined. Patients may still die from their disease, particularly in the early phases of treatment. Conversely, some patients appear not to require treatment and others respond well to splenectomy and need no further therapy. An individualized clinical approach is recommended, with a role for splenectomy in the patient with cytopenia and a relatively low number of hairy cells in the bone marrow. The first line drug treatment remains interferon alpha given for 12-18 months, following which the patient is observed for clinical relapse. Deoxycoformycin remains a useful experimental agent but cannot be recommended for routine clinical use until issues of long term toxicity are resolved. Chlorodeoxyadenosine is a very promising experimental drug, but confirmation of the early data in larger group trials is required. Similarly the adjunctive use of granulocyte colony stimulating factor appears useful, but will need further study in larger groups of patients. There is little or no role for alkylating agents or more intensive chemotherapy in the modern management of hairy-cell leukemia.
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PMID:Treatment of hairy-cell leukemia. 170 7

Several new cytostatic drugs have entered clinical phase I-II studies for the treatment of leukemia: the most promising are pyrimidine analogs such as 5-aza-cytidine, 5-aza-2'-deoxycytidine, 5-aza-cytosine arabinoside, and 2',2'-difluorodeoxycytidine. Fludarabine, a fluorinated purine analog, appears to be active in CLL and multiple myeloma. Deoxycoformycin, an adenosine analog, showed good activity in the treatment of hairy cell leukemia and T-cell neoplasias. 2-chloro-deoxyadenosine has recently been introduced into the treatment of CLL and hairy-cell leukemia refractory to deoxycoformicin. Tiazofurin, an antimetabolite which interferes with nicotine-adenine-dinucleotide (NAD) metabolism, has been applied in CML blast crisis. Other agents include 13-cis retinoic acid and 1, 25-dihydroxy vitamin D3 as differentiation inducers, and homoharringtonine, an alkylating agent which is widely used for ANLL treatment in China. Among new anthracyclines, aclarubicin, idarubicin, THP-adriamycin and fluoro-adriamycin should be mentioned. Mitoxantrone, a substituted anthraquinone, has successfully been applied in the treatment of relapsed and refractory ANLL. Amsacrine (m-AMSA), finally, is a synthetic aminoacridine which intercalates into DNA and inhibits DNA topoisomerase II. m-AMSA is not cross-resistant to anthracyclines and has been particularly active in ANLL treatment. Studies using m-AMSA alone or in combination revealed comparable results to anthracycline--containing regimens. Cardiotoxicity of the anthracycline congestive type has not been observed with m-AMSA. The EORTC Leukemia Cooperative Group has successfully used m-AMSA in several trials prepositioning this drug stepwise: from relapsed and refractory ANLL, into intensive maintenance treatment during first remission in ANLL, and, still on-going, into intensive consolidation.
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PMID:New drugs in the treatment of acute and chronic leukemia with some emphasis on m-AMSA. 206 23

2'-Deoxycoformycin (DCF) is an experimental drug with specific lymphocytotoxic activity which has proved effective in the treatment of some lymphoproliferative syndromes (LPS). This paper deals with the results achieved in 6 patients with LPS, five of them with T-cell and one with B-cell malignancies, who received DCF as initial (2 cases) or salvage (4 cases) therapy. One patient with adult T-cell leukaemia-lymphoma achieved complete remission maintained for 36 months of follow-up; partial remission was attained in three others and the remaining two patients failed to respond to the treatment. Kidney toxicity was seen in three cases, and in two of them it was necessary to stop the treatment. Kidney toxicity was seen in three cases, and in two of them it was necessary to stop the treatment. Other untoward effects included nausea and vomiting (2 patients), myoclonus, dysaesthesia of the limbs and conjunctivitis arida (one case each). No haematologic or infectious complications were present in association with DCF treatment.
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PMID:[Treatment of various lymphoproliferative syndromes with deoxycoformycin: results in 6 patients]. 208 59

Autologous bone marrow transplantation may contribute to the treatment of several types of lymphoreticular malignancies. Recent studies have suggested that a combination of chemoseparation and immunoseparation may be more effective than either modality alone in eliminating malignant cells from human bone marrow. In this report an immunotoxin has been prepared by conjugating pokeweed antiviral protein (PAP) to the 3A1 murine monoclonal antibody that recognizes a 40 kD (CD7) determinant expressed by most T cell acute lymphoblastic leukemias and a majority of normal mature peripheral T cells. When HSB-2 T lymphoma cells were mixed with normal human bone marrow and incubated with 3A1-PAP and 100 microM chloroquine, approximately 3 logs of clonogenic T cells could be eliminated from a 20-fold excess of bone marrow. Treatment of cell mixtures with 2'deoxycoformycin (2'-dCF) and deoxyadenosine (dAdo) eliminated 2 logs of clonogenic tumor cells. The use of 3A1-PAP and chloroquine with dCF/dAdo was more effective than either single modality, eliminating up to 6 logs of HSB-2 tumor cells in optimal experiments. Anti-tumor activity of the combined treatment extended to T leukemia cells taken directly from patients. Although 3A1-PAP reduced CFU-GM by only 13% and BFU-E by 36%, the addition of 2'-dCF and dAdo was more toxic for normal marrow precursors, further reducing CFU-GM, GEMM and BFU-E as well as preventing recovery of CFU-GM in long-term bone marrow culture.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Elimination of malignant clonogenic T cells from human bone marrow using chemoimmunoseparation with 2'-deoxycoformycin, deoxyadenosine and an immunotoxin. 236 80

The Eastern Cooperative Oncology Group conducted a study of pentostatin (2'-deoxycoformycin) in 37 patients with hairy-cell leukemia. Among the 27 patients who met all the study's entry criteria, the response rate was 96 percent, with 16 patients (59 percent) entering complete remission and 10 patients (37 percent) partial remission. In one patient no response was observed. These results were not significantly changed by the inclusion of nine additional patients who were found retrospectively not to have fulfilled the entry criteria. When complete remission was attained, maintenance therapy was not given. Despite this, no patient has had a relapse, and the duration of complete remission ranges from 1 to 375 days. Pentostatin appears to be equally effective in untreated patients and in those who have progressive disease after splenectomy or after both splenectomy and treatment with interferon. 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. Lengthy follow-up will be required to determine a median duration for the responses of hairy-cell leukemia to pentostatin.
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PMID:Remissions in hairy-cell leukemia with pentostatin (2'-deoxycoformycin). 243 50

2'-Deoxycoformycin (dCF), a potent adenosine deaminase inhibitor, has been reported to display greater toxicity for T than for B lymphoblasts. Since this compound can block DNA replication and since this effect is mediated by the intracellular ATP/dATP balance, its possible effect on DNA ligase was investigated. dCF at relatively low concentrations (1 microM), in association with dATP (100 microM), is a strong inhibitor of DNA ligase in T blasts, whereas it has no significant effect in B blasts at this concentration. The AMP-ligase complex is the target of the observed inhibition because the combined presence of the inhibitor and dATP results in a more stable dAMP-ligase complex. Because of this observation and of the greater adenosine deaminase activity observed in T cells, the dATP mediated dCF inhibition of ligase might be the crucial replication target of T cell toxicity. These observations are discussed in terms of T immunodeficiencies including Graft Versus Host Disease and related syndromes.
Leukemia 1989 Feb
PMID:dATP-mediated inhibition of DNA ligase by 2'-deoxycoformycin in T and B cell leukemia. 278 73

A new antimetabolite, 2'-deoxycoformycin (pentostatin), has striking antitumor activity in several lymphoid neoplasms. Isolated from cultured soil organisms, this purine analogue is a potent inhibitor of adenosine deaminase (ADA), and is thus selectively toxic to lymphocytes. Early clinical trials showed that high doses of pentostatin caused severe and unpredictable toxicity, but responses in refractory lymphoid malignancies were encouraging. Careful pharmacologic studies led to the definition of a safe and effective low weekly dose, at which protracted ADA inhibition occurs in neoplastic cells. The most sensitive tumor identified is hairy cell leukemia, in which durable remissions are achieved in more than 90% of patients with a relatively brief course of treatment. Other responsive diseases include chronic lymphocytic leukemia, prolymphocytic leukemia, mycosis fungoides, and acute T-cell lymphoma or leukemia. Response has been seen in acute lymphocytic leukemia, but the higher doses required are substantially more toxic. Pentostatin is valuable for treatment of indolent lymphoid malignancies and may be useful in non-cancer-related lymphocyte research.
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PMID:2'-Deoxycoformycin (pentostatin) for lymphoid malignancies. Rational development of an active new drug. 328 67


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