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Clinical Lymphoma Nov 2000Cutaneous T-cell lymphoma (CTCL) includes a heterogeneous group of diseases manifested in many cases by a prolonged clinical course. Even patients with advanced clinical... (Review)
Review
Cutaneous T-cell lymphoma (CTCL) includes a heterogeneous group of diseases manifested in many cases by a prolonged clinical course. Even patients with advanced clinical disease, including erythroderma, adenopathy, and cutaneous tumors, can respond to a number of conservative therapeutic modalities, including radiation, cutaneous and extracorporeal phototherapy, and interferon. More aggressive systemic therapies are generally reserved for patients with visceral involvement or effaced (LN4) lymph node disease or patients refractory to multiple conservative approaches. Since no survival benefit has been demonstrated for multiagent cytotoxic chemotherapy regimens, this therapy is generally reserved for patients whose disease demonstrates an aggressive clinical course requiring immediate palliation. Durable responses (5+ years) have been reported with purine analogues; however, prolonged immunosuppression and increased frequency of opportunistic infections have been demonstrated. Novel therapeutic agents, including interleukin-2, interleukin-12, the phosphorylase inhibitor peldesine (BCX-34), and bexarotene, have demonstrated activity. The interleukin-2 diphtheria toxin fusion protein, DAB(389)IL-2, has demonstrated a 30% response rate in advanced and refractory CTCL patients. The optimal role of targeted biological therapies in advanced patients will likely be in the minimal disease setting following either chemotherapy or radiation.
Topics: Humans; Lymphoma, T-Cell, Cutaneous; Medical Oncology; Skin Neoplasms
PubMed: 11707857
DOI: 10.3816/clm.2000.s.002 -
BCX-34: a novel T-cell selective immunosuppressant: purine nucleoside phosphorylase (PNP) inhibitor.Artificial Organs Aug 1996We evaluated the efficacy of a new purine nucleoside phosphorylase inhibitor, BCX-34, as an immunosuppressive agent. BCX-34 showed a complete inhibitory effect on the...
We evaluated the efficacy of a new purine nucleoside phosphorylase inhibitor, BCX-34, as an immunosuppressive agent. BCX-34 showed a complete inhibitory effect on the proliferation of T-cells in an in vitro system, whereas no influence was observed in B-cell lines. In addition, it was revealed that this inhibitory effect was not due to the suppression of interleukin-2 production. Therefore, BCX-34 might be a potentially useful drug that can be used in combination, not competition, with cyclosporine A and FK506.
Topics: Animals; B-Lymphocytes; Cell Division; Cells, Cultured; Cyclosporine; Drug Synergism; Guanine; Humans; Immunosuppressive Agents; Interleukin-2; Jurkat Cells; Leukemia, T-Cell; Mice; Purine-Nucleoside Phosphorylase; T-Lymphocytes; Tacrolimus; Tumor Cells, Cultured
PubMed: 8853794
DOI: 10.1111/j.1525-1594.1996.tb04557.x -
Brain Research Mar 1999Murine spinal cord primary mixed cultures were treated with the respiratory inhibitor, rotenone, to mimic hypoxic conditions. Under these conditions neurons rapidly...
Murine spinal cord primary mixed cultures were treated with the respiratory inhibitor, rotenone, to mimic hypoxic conditions. Under these conditions neurons rapidly underwent oncosis (necrosis) with a complete loss in viability occurring within 260 min; however, astrocytes, which accounted for most of the cell population, died more slowly with 50% viability occurring at 565 min. Inosine preserved both total cell and neuronal viability in a concentration-dependent manner. The time of inosine addition relative to hypoxic insult was critical with the most effective protection occurring when inosine was added just prior to or within 5 min after insult. Inosine was ineffective when added 30 min after hypoxic insult. The effect of guanosine was similar to that of inosine. Treatment of cultures with BCX-34, a purine nucleoside phosphorylase inhibitor, prevented protection by inosine or guanosine, suggesting involvement of a purine nucleoside phosphorylase in the nucleoside protective effect.
Topics: Anaerobiosis; Animals; Astrocytes; Cell Hypoxia; Cell Respiration; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glucose; Glycolysis; Guanine; Guanosine; Inosine; Mice; Neurons; Purine-Nucleoside Phosphorylase; Spinal Cord
PubMed: 10064830
DOI: 10.1016/s0006-8993(99)01086-0 -
Chemical Research in Toxicology Dec 2003Sodium arsenite is much more potent than sodium arsenate in producing adverse effects in animals and in cultured cells. Although arsenate may exhibit toxicity as a... (Comparative Study)
Comparative Study
Sodium arsenite is much more potent than sodium arsenate in producing adverse effects in animals and in cultured cells. Although arsenate may exhibit toxicity as a phosphate analogue, its potency in vivo appears to be enhanced by reduction to arsenite. To understand the relative importance of this reduction, which is critical in evaluating the responsiveness of cell culture models to the different oxidation states and thus to elucidating the mechanism of arsenic action, present work has correlated the extent of reduction with biological activity in human keratinocytes. The results show that at biologically relevant concentrations, arsenate reduction to appreciable levels required several days, helping rationalize a previous empirical observation that it was approximately one-third as potent as arsenite. The relatively low conversion rate also emphasizes a limitation of culture; arsenate was nearly as efficacious as arsenite, but the time required for it to reach maximal effect exceeded ordinary medium change intervals. In keratinocytes, an important role for purine nucleoside phosphorylase in the reduction could not be demonstrated, indicating that another pathway is dominant in this cell type. Methylation of inorganic arsenic, uptake of methylated forms, and their reduction were all very slow. These findings suggest that the reduced methylated forms have only a small contribution to skin carcinogenesis unless they are supplied through the circulation. In parallel experiments, trivalent antimony was similar to arsenite in potency and efficacy, whereas pentavalent antimony was virtually without biological effect. Conversion of antimony in the pentavalent to the trivalent oxidation state was not detectable in keratinocytes. These findings emphasize the importance of intracellular reduction of the metalloids for biological effects.
Topics: Animals; Antimony; Arsenic; Biotransformation; Cattle; Cell Line; Dose-Response Relationship, Drug; Enzyme Induction; Enzyme Inhibitors; Fibroblasts; Guanine; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Humans; Keratinocytes; Membrane Proteins; Oxidation-Reduction; Protein Precursors; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Pyrimidinones; Pyrroles; Spleen
PubMed: 14680377
DOI: 10.1021/tx034146y -
Immunopharmacology Jul 1998The antiproliferative effect of BCX-34 was tested in normal human peripheral blood mononuclear cells (PBMCs) induced to proliferate with OKT3, tetanus toxoid, the mixed...
The antiproliferative effect of BCX-34 was tested in normal human peripheral blood mononuclear cells (PBMCs) induced to proliferate with OKT3, tetanus toxoid, the mixed lymphocyte reaction, or IL-2. In the case of OKT3, tetanus toxoid, or the MLR the IC50s ranged between 0.7 and 4 microM. With IL-2, the IC50 was 14.6 microM. In T-cells purified by rosetting the IC50 with IL-2 was 0.62 microM. In CD4 or CD8 cells obtained by magnetic activated cell sorting the IC50s with IL-2 were 0.24 and 0.62 microM, respectively. BCX-34 inhibition of proliferation in human PBMCs may not depend entirely upon the accumulation of intracellular dGTP because tetanus toxoid-induced proliferation was inhibited in the absence of deoxyguanosine and was not reversed by deoxycytidine. BCX-34 did not inhibit IL-2 release from PBMCs and did not alter PBMC viability. The results of these studies show that BCX-34 is a potent inhibitor of normal human T-cell proliferation induced by antigenic or IL-2 stimulation. BCX-34 in normal human T-cells has a deoxyguanosine-independent mechanism to suppress in vitro proliferation. BCX-34 appears to have little effect on T-cell viability. The data suggest that BCX-34 may be useful in the treatment of T-cell proliferative disorders.
Topics: Cell Division; Cell Survival; Dose-Response Relationship, Drug; Enzyme Inhibitors; Guanine; Humans; Immunosuppressive Agents; Interleukin-2; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Muromonab-CD3; Purine-Nucleoside Phosphorylase; T-Lymphocytes; Tetanus Toxin
PubMed: 9776473
DOI: 10.1016/s0162-3109(98)00012-5 -
Immunopharmacology Oct 1996BCX-34 inhibits RBC PNP in vitro from humans, rats, and mice with IC50S ranging from 5 to 36 nM. BCX-34 also, in the presence but not in the absence of deoxyguanosine,...
BCX-34 inhibits RBC PNP in vitro from humans, rats, and mice with IC50S ranging from 5 to 36 nM. BCX-34 also, in the presence but not in the absence of deoxyguanosine, inhibits human CCRF-CEM T-cell proliferation with an IC50 of 0.57 microM but not rat or mouse T-cell proliferation up to 30 microM. Inhibition of human T-cell proliferation is accompanied by an accumulation of intracellular dGTP with an associated reduction in GTP. These nucleotide changes do not occur in BC16A mouse T-cells and explain why proliferation is not inhibited by PNP inhibitors in this case. Reduction in intracellular GTP is not essential for the antiproliferative action of BCX-34. Oral bioavailability of BCX-34 in rats is 76%. BCX-34 is orally active in elevating plasma inosine in rats (2-fold at 30 mg/kg), in suppressing ex vivo RBC PNP activity in rats (98% at 3 h. 100 mg/kg), and in suppressing ex vivo skin PNP in mice (39% at 3 h, 100 mg/kg). The results demonstrate that BCX-34 inhibits human PNP and T-cell proliferation, is orally bioavailable in rodents, and pharmacologically active in vivo in rodents after oral dosing with no apparent side effects or toxicity. BCX-34 may, therefore, be useful in treating human T-cell proliferative inflammatory disorders.
Topics: Animals; Cells, Cultured; Deoxyguanine Nucleotides; Guanine; Guanosine Triphosphate; Humans; Immunosuppressive Agents; Lymphocyte Activation; Lymphoma, T-Cell; Mice; Purine-Nucleoside Phosphorylase; Rats; T-Lymphocytes; Tumor Cells, Cultured
PubMed: 8913795
DOI: 10.1016/0162-3109(96)00123-3 -
The British Journal of Dermatology May 2014The authors performed a systematic review of randomized controlled trials (RCTs) on interventions for any stage of typical mycosis fungoides (MF). They searched...
BACKGROUND
The authors performed a systematic review of randomized controlled trials (RCTs) on interventions for any stage of typical mycosis fungoides (MF). They searched electronic databases including the Cochrane Central Register of Controlled Trials, Medline, Embase, and the Latin American and Caribbean Health Science Information database, and included reports from conference proceedings and unpublished data without language restrictions. The authors also searched trial registries affiliated with the U.S.A., Australia, the World Health Organization and the European Organisation of Research and Treatment of Cancer for studies on 'mycosis fungoides' or 'cutaneous T-cell lymphoma'. These searches were supplemented by correspondence with the groups or individuals who conducted the RCTs.
METHODS
The authors included RCTs with participants who were 18 years of age or older, that had staging information, and in which > 90% of patients had biopsy-proven typical CD4+ MF. Data on treatment and outcome of participants, including information on stage of MF, therapy, quality of life, remission or improvement, duration of remission, survival, adverse effects and toxicity were obtained from included studies. Primary outcomes were adverse effects and quality of life. Secondary outcomes were clearance of at least 90% of surface area involvement, improvement of at least 50% of surface area involvement, survival rate, relapse rate and disease-free interval. The authors also recorded potentially significant participant-related prognostic factors, such as age and sex, and tumour-related prognostic factors, such as histological subtype and systemic involvement.
FINDINGS
From 407 unique references, 14 RCTs were included with a total of 675 patients. These trials included skin-directed therapies [topical peldesine, topical imiquimod, topical hypericin, intralesional interferon (IFN)-α, psoralen ultraviolet A (PUVA) therapy, electron-beam therapy (EBT) and local radiation], systemic therapies [extracorporeal photopheresis (ECP), denileukin diftitox, bexarotene] and combination therapies (injected transfer factor with concomitant topical nitrogen mustard use). Only one meta-analysis of two studies comparing PUVA with IFN-α vs. PUVA alone could be performed, and no significant differences between the two therapies were found. Two studies on intralesional IFN-α vs. placebo were included in the review and provided opposing results, but were not examined by meta-analysis due to differences in their study design. The remainder of the Cochrane analysis reviewed outcomes of individual RCTs. There were statistically significant differences in improvement or clearance for five therapeutic regimens. One trial of topical hypericin vs. placebo found a relative benefit of hypericin, risk ratio (RR) for improvement 7·00, 95% confidence interval (CI) 1·01-48·54, P ≤ 0·028. A trial comparing ECP with PUVA demonstrated significantly better improvement in the PUVA group (RR 0·07, 95% CI 0·00-1·00, P ≤ 0·002). An RCT examining 'conservative', stepwise escalation from topical nitrogen mustard to 'combination therapy' with EBT and cyclophosphamide, doxorubicin, etoposide and vincristine chemotherapy found that combination therapy was superior in clearance (RR 2·18, 95% CI 1·10-4·33, P ≤ 0·03) and improvement (RR 1·40, 95% CI 1·12-1·74, P ≤ 0·003). However, there were no statistically significant differences in survival rates at a median follow-up of 75 months. A comparison of subcutaneously injected IFN-α and acitretin vs. subcutaneously injected IFN-α and PUVA found increased clearance with IFN-α and PUVA (RR 0·54, 95% CI 0·35-0·84, P ≤ 0·005). There were also significant reductions in grade III, severe adverse events on the World Health Organization scale; events requiring discontinuation; and neurological disorders in the IFN-α plus PUVA group. Finally, a trial comparing active vs. inactivated transfer factor found significant differences between the groups, favouring inactivated transfer factor (Fisher's exact test, P ≤ 0·03, RR 0·09, 95% CI 0-0·61). The original study authors speculated that their results reflected a better initial prognosis for the group receiving inactivated transfer factor. None of the interventions assessed showed significant long-term benefit. Despite significantly superior clearance rates in four trials, participants in those studies had high relapse rates.
INTERPRETATION
This review of RCTs for MF interventions led to more questions than answers due to a dearth of adequately powered RCTs. Only one meta-analysis could be performed. The remaining review was based on single trials, many of which assessed infrequently used treatments or regimens and are not reflective of current clinical practices. Only two of the 14 RCTs assessed patient health-related quality-of-life outcomes.
Topics: Humans; Mycosis Fungoides; Skin Neoplasms
PubMed: 24841586
DOI: 10.1111/bjd.12954 -
Transplantation Proceedings Jun 1998
Topics: Animals; Cell Line, Transformed; Deoxyguanosine; Enzyme Inhibitors; Guanine; Humans; Immunosuppressive Agents; Interleukin-2; Jurkat Cells; Kinetics; Lymphocyte Culture Test, Mixed; Mice; Mice, Inbred C57BL; Purine-Nucleoside Phosphorylase; Rats; Rats, Inbred F344; Spleen; T-Lymphocytes
PubMed: 9636397
DOI: 10.1016/s0041-1345(98)00119-5 -
Human Research Report May 2006
Topics: Clinical Trials as Topic; Consent Forms; Ethics Committees, Research; Female; Guanine; Guideline Adherence; Humans; Mandatory Reporting; Neoplasms; Research Design; Research Personnel; Research Subjects; United States; United States Office of Research Integrity; Universities
PubMed: 16832916
DOI: No ID Found -
Journal of Chromatography. B,... Mar 19979-(3-Pyridylmethyl)-9-deazaguanine (BCX-34), a new purine nucleoside phosphorylase inhibitor, has selective immunosuppressive activity with potential therapeutic value... (Clinical Trial)
Clinical Trial
9-(3-Pyridylmethyl)-9-deazaguanine (BCX-34), a new purine nucleoside phosphorylase inhibitor, has selective immunosuppressive activity with potential therapeutic value in T-cell-mediated disease. We now report a sensitive, specific and reproducible method for measurement of 9-(3-pyridylmethyl)-9-deazaguanine in biological fluids using high-performance liquid chromatography (HPLC). 9-(3-Pyridylmethyl)-9-deazaguanine was extracted from plasma using perchloric acid precipitation followed by passage through Sep-Pak C18 cartridges (average extraction efficiency, 64.6%). Standard curves were linear over the range of interest (28-1120 ng/ml in plasma and 200-4000 ng/ml in urine, r2 > 0.999). Within-day and between-day coefficients of variation were less than 8%. The limit of quantitation was 28 ng/ml in plasma and 200 ng/ml in urine. This HPLC method should be useful in future clinical studies with this drug.
Topics: Administration, Oral; Chromatography, High Pressure Liquid; Guanine; Humans; Immunosuppressive Agents; Infusions, Intravenous; Lymphoma, T-Cell, Cutaneous; Purine-Nucleoside Phosphorylase; Reproducibility of Results; Sensitivity and Specificity; Skin Neoplasms
PubMed: 9106056
DOI: 10.1016/s0378-4347(96)00365-9