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Toxins Jun 2020Ascomycete fungi such as , , and have been mass produced on artificial media either as food supplements or health additives while the byproducts of culture substrates... (Review)
Review
Ascomycete fungi such as , , and have been mass produced on artificial media either as food supplements or health additives while the byproducts of culture substrates are largely used as animal feed. The safety concerns associated with the daily consumption of fungi or related products are still being debated. On the one hand, the known compounds from these fungi such as adenosine analogs cordycepin and pentostatin have demonstrated different beneficial or pharmaceutical activities but also dose-dependent cytotoxicities, neurological toxicities and or toxicological effects in humans and animals. On the other hand, the possibility of mycotoxin production by fungi has not been completely ruled out. In contrast to a few metabolites identified, an array of biosynthetic gene clusters (BGCs) are encoded in each genome of these fungi with the potential to produce a plethora of as yet unknown secondary metabolites. Conservation analysis of BGCs suggests that mycotoxin analogs of PR-toxin and trichothecenes might be produced by fungi. Future elucidation of the compounds produced by these functionally unknown BGCs, and in-depth assessments of metabolite bioactivity and chemical safety, will not only facilitate the safe use of fungi as human food or alternative medicine, but will also benefit the use of mass production byproducts as animal feed. To corroborate the long record of use as a traditional medicine, future efforts will also benefit the exploration of fungi for pharmaceutical purposes.
Topics: Animal Feed; Animals; Consumer Product Safety; Cordyceps; Dietary Supplements; Food Microbiology; Humans; Industrial Microbiology; Mycotoxins; Risk Assessment
PubMed: 32575649
DOI: 10.3390/toxins12060410 -
Cancer Treatment Reviews Oct 2014Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas with a very poor prognosis. Current therapies, based on... (Review)
Review
Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas with a very poor prognosis. Current therapies, based on historical regimens for aggressive B-cell lymphomas, have resulted in insufficient patient outcomes. The majority of patients relapse rapidly, and current 5-year overall survival rates are only 10-30%. It is evident that new approaches to treat patients with PTCL are required. In recent years, prospective studies in PTCL have been initiated, mainly in patients with relapsed/refractory disease. In some of these, selected histologic subtypes have been evaluated in detail. As a consequence, numerous new therapies have been developed and shown activity in PTCL, including: agents targeting the immune system (e.g. brentuximab vedotin, alemtuzumab, lenalidomide); histone deacetylase inhibitors (romidepsin, belinostat); antifolates (pralatrexate); fusion proteins (denileukin diftitox); nucleoside analogs (pentostatin, gemcitabine); and other agents (e.g. alisertib, plitidepsin, bendamustine, bortezomib). A variety of interesting novel combinations is also emerging. It is hoped that these innovative approaches, coupled with a greater understanding of the clinicopathologic features, pathogenesis, molecular biology, and natural history of PTCL will advance the field and improve outcomes in this challenging group of diseases. This review summarizes the currently available clinical evidence on the various approaches to treating relapsed/refractory PTCL, including the role of stem cell transplantation, with an emphasis on potential new drug therapies.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brentuximab Vedotin; Cyclophosphamide; Depsipeptides; Diphtheria Toxin; Doxorubicin; Folic Acid Antagonists; Histone Deacetylase Inhibitors; Humans; Immunoconjugates; Interleukin-2; Lenalidomide; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local; Peptides, Cyclic; Prednisolone; Recombinant Fusion Proteins; Stem Cell Transplantation; Thalidomide; Topoisomerase Inhibitors; Vincristine
PubMed: 25199959
DOI: 10.1016/j.ctrv.2014.08.001 -
Molecules (Basel, Switzerland) Mar 2009For the past few years more and more new cytotoxic agents active in the treatment of hematological malignancies have been synthesized and become available for either in... (Review)
Review
For the past few years more and more new cytotoxic agents active in the treatment of hematological malignancies have been synthesized and become available for either in vitro studies or clinical trials. Among them the class of antineoplastic drugs belonging to the purine nucleoside analogues group (PNAs) plays an important role. Three of them: pentostatin (DCF), cladribine (2-CdA) and fludarabine (FA) were approved by Food and Drug Administration (FDA) for the treatment of hematological malignancies. Recently three novel PNAs: clofarabine (CAFdA), nelarabine (ara-G) and forodesine (immucillin H, BCX-1777) have been synthesized and introduced into preclinical studies and clinical trials. These agents seem to be useful mainly for the treatment of human T-cell proliferative disorders and they are currently undergoing clinical trials in lymphoid malignancies. However, there are also several studies suggesting the role of these drugs in B-cell malignancies. This review will summarize current knowledge concerning the mechanism of action, pharmacologic properties, clinical activity and toxicity of PNAs accepted for use in clinical practice, as well as new agents available for clinical trials.
Topics: Antineoplastic Agents; Humans; Lymphoproliferative Disorders; Purine Nucleosides; Treatment Outcome
PubMed: 19325518
DOI: 10.3390/molecules14031183 -
Henry Ford Hospital Medical Journal 1991Adenosine deaminase (ADA), a purine salvage pathway enzyme, appears to play a key role in normal lymphocyte growth, development, and differentiation. Three new purine... (Review)
Review
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.
Topics: 2-Chloroadenosine; Antineoplastic Agents; Cladribine; Clinical Trials as Topic; Deoxyadenosines; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Vidarabine
PubMed: 1679757
DOI: No ID Found -
Best Practice & Research. Clinical... Dec 2015Since 2006 when we last reviewed the literature concerning the use of purine analogues in hairy cell leukaemia (HCL), results from several new and updated series have... (Review)
Review
Since 2006 when we last reviewed the literature concerning the use of purine analogues in hairy cell leukaemia (HCL), results from several new and updated series have been published. Here we examine these reports and consider their implications for patient management. The two purine analogues pentostatin and cladribine remain the first-line treatments of choice for all patients with HCL. Although they have not been compared in randomised trials, they appear to be equally effective. A complete response is important for the long-term outcome and we look at how best this can be achieved. Evidence is emerging which supports the use of either purine analogue plus an anti-CD20 monoclonal antibody after relapse, though questions remain concerning the scheduling of the monoclonal antibody. Patients refractory to the purine analogues may require alternative agents.
Topics: Antineoplastic Agents; B-Lymphocytes; Cladribine; Follow-Up Studies; Humans; Indoles; Leukemia, Hairy Cell; Mutation; Pentostatin; Prognosis; Proto-Oncogene Proteins B-raf; Recurrence; Remission Induction; Rituximab; Sulfonamides; Survival Analysis; Vemurafenib
PubMed: 26614900
DOI: 10.1016/j.beha.2015.09.004 -
The Journal of Biological Chemistry Aug 1984The biochemical and metabolic effects of deoxycoformycin, a potent inhibitor of adenosine deaminase, were investigated using two human T lymphoblastoid cell lines. A...
The biochemical and metabolic effects of deoxycoformycin, a potent inhibitor of adenosine deaminase, were investigated using two human T lymphoblastoid cell lines. A dose-response analysis demonstrated that the concentration of deoxycoformycin at which there was 50% inhibition of growth was greater than 1 X 10(-3) M in lymphoblastoid cells. Uptake of deoxycoformycin was biphasic and occurred much more slowly than for natural nucleosides, and lower saturation levels were reached. The intracellular concentration of deoxycoformycin achieved was 0.4 to 0.5 microM when the extracellular concentration was 1 microM. At 10 microM extracellular concentration, the intracellular concentration was 3-4 microM. Although deoxycoformycin at very low concentrations (1 or 10 microM) did not have any detectable effects on the growth of these cells, the nucleoside was found to be metabolized, and was phosphorylated to give the mono-, di-, and triphosphate derivatives. The triphosphate derivative was incorporated into cellular DNA with little incorporation into cellular RNA. Metabolism of deoxycoformycin in several mutant lymphoblastoid cells deficient in adenosine kinase and/or deoxycytidine kinase was found to be unchanged from wild-type cells, indicating that these major nucleoside kinases do not play a significant role in the phosphorylation of deoxycoformycin. These results may account, at least in part, for the differences that are observed between the pharmacologic inhibition of adenosine deaminase, and the inherited deficiency of adenosine deaminase.
Topics: Adenosine Deaminase Inhibitors; Adenosine Kinase; Chromatography, High Pressure Liquid; Coformycin; DNA; Deoxyadenine Nucleotides; Deoxyadenosines; Deoxycytidine Kinase; Humans; Nucleoside Deaminases; Pentostatin; Phosphorylation; RNA; Ribonucleosides; T-Lymphocytes; Vidarabine
PubMed: 6204981
DOI: No ID Found -
Clinical Cancer Research : An Official... Mar 2016Immunotoxins are targeted anticancer therapeutics that kill cancer cells using a cytotoxic bacterial toxin payload. Their development for use in solid tumor malignancies...
Immunotoxins are targeted anticancer therapeutics that kill cancer cells using a cytotoxic bacterial toxin payload. Their development for use in solid tumor malignancies was delayed due to issues with their immunogenicity and limited therapeutic window. However, new research has rejuvenated the field. Coadministration with a lymphocyte-depleting regimen of pentostatin and cyclophosphamide can delay antidrug antibody formation, increasing the number of treatment cycles that patients can receive and resulting in durable responses in heavily pretreated patients. In addition, a new generation of immunotoxin molecules with reduced immunogenicity and nonspecific toxicity has been developed through protein engineering techniques, and one has recently entered the clinic. In preclinical studies in mouse models, these new agents are effective against many tumor types as single agents, and also produce synergistic antitumor responses in combination with chemotherapy. These new immunotoxins have renewed excitement in the field and may prove a promising addition to the targeted therapy repertoire.
Topics: ADP Ribose Transferases; Animals; Antibodies, Monoclonal; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Bacterial Toxins; Cyclophosphamide; Disease Models, Animal; Exotoxins; Humans; Immunotherapy; Lymphocytes; Mesothelioma; Mice; Pentostatin; Virulence Factors; Pseudomonas aeruginosa Exotoxin A
PubMed: 26463707
DOI: 10.1158/1078-0432.CCR-15-1623 -
Annals of Oncology : Official Journal... 1996The observation of lymphopenia in children deficient in adenosine deaminase (ADA) led to exploration of an inhibitor of the enzyme in lymphoid malignancies; thus... (Review)
Review
The observation of lymphopenia in children deficient in adenosine deaminase (ADA) led to exploration of an inhibitor of the enzyme in lymphoid malignancies; thus deoxycoformycin was the first purine nucleotide used in human trials. Fludarabine and 2-chlorodeoxyadenosine (2-CdA), agents resistant to deamination by ADA, have been utilized in the past decade. All of these drugs act as competitors for deoxyadenosine triphosphate at the A sites of the elongating DNA strand, terminating DNA synthesis. However, their remarkable efficacy in indolent lymphoid malignancies is not well explained by this mechanism of action. The induction of apoptosis and resultant cytotoxicity may be important in their activity. As a single agent, fludarabine has been associated with overall remission rates as high as 55% in previously treated patients and 79% in previously untreated patients. With this agent, a dosage regimen of 25-30 mg/m2 daily over 5 days seems to be the most effective to date. Fludarabine has shown more favorable remission rates than the traditional salvage regimens incorporating anthracyclines and alkylating agents. Regimens combining fludarabine with mitoxantrone and with doxorubicin have shown minimal therapeutic advantage in CLL, while combination with cyclophosphamide appears promising. Remission rates with deoxycoformycin have been lower than with fludarabine, but studies have been small in patient numbers. The agent 2-CdA, first successful in hairy-cell leukemia, has shown overall response rates in chronic lymphocytic leukemia similar to those seen with fludarabine. Whether or not cross-resistance occurs among the purine analogs has not been fully determined, but occasional patients with disease refractory to fludarabine have responded to 2-CdA. Cumulative myelosuppression and immunosuppression may be experienced however. In the B-cell neoplastic entity, Waldenström's macroglobulinemia, fludarabine therapy in patients previously treated with alkylating agents and/or steroids produced a 36% response rate. Only two previously untreated patients received fludarabine, and both responded. A similar response rate of 40% was seen when 2-CdA was administered to previously treated patients. This response rate increased to 85% in a study of 26 previously untreated patients, making this one of the most effective drugs yet investigated in this condition.
Topics: Antineoplastic Agents; Cladribine; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Purine Nucleosides; Vidarabine; Waldenstrom Macroglobulinemia
PubMed: 9010576
DOI: 10.1093/annonc/7.suppl_6.s27 -
Clinical Journal of the American... Sep 2016The monoclonal gammopathies of renal significance (MGRS) are a group of disorders characterized by monoclonal Ig deposition in the kidney, but are not associated with... (Review)
Review
The monoclonal gammopathies of renal significance (MGRS) are a group of disorders characterized by monoclonal Ig deposition in the kidney, but are not associated with systemic lymphoma or overt multiple myeloma. The prevailing hypothesis is that the pathogenic paraproteins in MGRS are produced by underlying B cell or plasma cell clones. However, in the MGRS literature, the yield of detecting a clone has been variable, and progression to ESRD is common. Here, we present an "onco-nephrologic" approach to the MGRS disorders by highlighting recent advances in lymphoma and multiple myeloma that can be used in the evaluation and management of these patients.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bortezomib; Cyclophosphamide; Dexamethasone; Humans; Immunoglobulins; Immunosuppressive Agents; Kidney Diseases; Lenalidomide; Melphalan; Oligopeptides; Paraproteinemias; Pentostatin; Rituximab; Thalidomide; Vidarabine
PubMed: 27416775
DOI: 10.2215/CJN.03160316 -
Pharmacotherapy Jan 2022Alemtuzumab is a monoclonal antibody that targets the cell surface antigen CD52 on lymphocytes. Although it is used for the treatment of hematologic malignancies, such... (Clinical Trial)
Clinical Trial
STUDY OBJECTIVE
Alemtuzumab is a monoclonal antibody that targets the cell surface antigen CD52 on lymphocytes. Although it is used for the treatment of hematologic malignancies, such as chronic lymphocytic leukemia, and incorporated into many hematopoietic stem cell transplant (HSCT) conditioning regimens, few studies have evaluated the pharmacology of alemtuzumab in adult patients with sickle cell disease (SCD). We therefore examined the pharmacokinetics (PK) and pharmacodynamics (PD) of alemtuzumab in adults with SCD who received a matched related donor HSCT to determine if the clearance of alemtuzumab affects transplant outcomes.
DESIGN
PK and PD analysis of patient data from a single-center clinical trial.
SETTING
Clinical research center.
PATIENTS
Twenty-two adult patients with SCD who received one of two nonmyeloablative allogeneic HSCT regimens: alemtuzumab and total body irradiation (Alem-TBI) or pentostatin, cyclophosphamide, alemtuzumab, and total body irradiation (Pento-Cy-Alem-TBI).
MEASUREMENTS AND MAIN RESULTS
Alemtuzumab serum concentrations, absolute lymphocyte counts, T-cell (CD3), and myeloid (CD14/15) chimerism were collected at distinct time points and analyzed. A semi-mechanistic PK population model was built to understand inter-individual differences in pharmacology. Alemtuzumab was detectable up to 28 days post-HSCT. The mean alemtuzumab level 7 days after transplant for patients on Alem-TBI was 818 ng/ml, significantly lower than the mean level of 1502 ng/ml for patients on Pento-Cy-Alem-TBI (p < 0.001), but this difference decreased as time progressed. The clearance of alemtuzumab was linear, and the half-life was longer in the Pento-Cy-Alem-TBI group (average half-life = 61.1 h) compared to the Alem-TBI group (average half-life = 44.1 h) (p < 0.001). The CD3 chimerism at 2 and 4 months after transplant positively correlated with alemtuzumab levels collected on day 14 after transplant (R = 0.40 and p = 0.004 at 2 months, R = 0.36 and p = 0.005 at 4 months), but this significance was lost by 6 months after HSCT. No correlation was seen between alemtuzumab levels and CD14/15 chimerism.
CONCLUSION
Between 2 and 4 months after transplant, higher alemtuzumab levels measured 14 days after transplant correlated with patients having better engraftment, suggesting more lymphodepletion may be needed to reduce graft failure in these two non-myeloablative matched related donor HSCT regimens.
Topics: Adult; Alemtuzumab; Anemia, Sickle Cell; Chimerism; Drug Elimination Routes; Hematopoietic Stem Cell Transplantation; Humans; Lymphocyte Count; T-Lymphocytes
PubMed: 34669981
DOI: 10.1002/phar.2641