pyrimidinones and Lymphoma

Purine nucleoside phosphorylase (PNP) is a key enzyme in the purine-salvage metabolic pathway. In humans, the loss of functional PNP results in significant T-cell-mediated immunodeficiency (and may also affect B-cell function). Forodesine is a potent PNP inhibitor that acts by elevating plasma 2'-deoxyguanosine (dGuo) and intracellular deoxyguanosine triphosphate, which in turn affects deoxynucleotide-triphosphate pools and induces cell death by apoptosis. BioCryst Pharmaceuticals Inc, under license from the Albert Einstein College of Medicine, is developing intravenous and oral formulations of forodesine for the potential treatment of various T-cell and B-cell lymphomas and leukemias, as well as for solid tumors; MundiPharma AG is also investigating the drug for leukemia. Forodesine effectively inhibits T-cell proliferation in vitro in the presence of dGuo. In early clinical trials, forodesine has demonstrated an acceptable safety profile and indications of biological activity. Few drug-related serious adverse events have been reported, and generally only mild-to-moderate nonhematological toxicity has been observed. Forodesine has the potential to lead the development of other novel therapies with broad-based activity for hematological malignancies; the drug may also be useful for the treatment of a wide variety of other T-cell-mediated disorders, as well as for the potential treatment for other B-cell lymphomas/leukemias.

Topics: Animals; Enzyme Inhibitors; Humans; Leukemia; Lymphoma; Neoplasms; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Pyrimidinones; Structure-Activity Relationship

Topics: Adolescent; Adult; Animals; Bleomycin; Bone Marrow; Bone Marrow Transplantation; Cell Separation; Child; Child, Preschool; Clinical Trials as Topic; Cyclophosphamide; Drug Evaluation; Etoposide; Graft vs Host Disease; Hematopoietic Stem Cells; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Lysophosphatidylcholines; Methylprednisolone; Neoplasms, Experimental; Phospholipid Ethers; Pyrimidinones; Transplantation, Autologous; Transplantation, Isogeneic

Topics: Acute Disease; Animals; Bone Marrow; Bone Marrow Transplantation; Cyclophosphamide; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Leukemia; Lymphoma; Mechlorethamine; Neoplastic Stem Cells; Photosensitivity Disorders; Podophyllotoxin; Pyrimidinones; Rats; Transplantation, Autologous

Substantial preclinical evidence and case reports suggest that MEK inhibition is an active approach in tumors with. The NCI-MATCH study performed genomic profiling on tumor samples from patients with solid tumors and lymphomas progressing on standard therapies or with no standard treatments. Patients with prespecified fusions and non-V600 mutations in. Among 50 patients assigned, 32 were eligible and received therapy with trametinib. Of these, 1 had a. Trametinib did not show promising clinical activity in patients with tumors harboring non-V600

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Lymphoma; Male; Middle Aged; Mutation; National Cancer Institute (U.S.); Neoplasms; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Rate; Treatment Outcome; United States

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bendamustine Hydrochloride; Boronic Acids; Bortezomib; Brentuximab Vedotin; Diphtheria Toxin; Drug Discovery; Everolimus; Humans; Hydroxamic Acids; Immunoconjugates; Indoles; Inotuzumab Ozogamicin; Interleukin-2; Lenalidomide; Lymphoma; Lymphoma, B-Cell; Nitrogen Mustard Compounds; Purine Nucleosides; Pyrazines; Pyrimidinones; Recombinant Fusion Proteins; Sirolimus; Thalidomide; Vorinostat

To investigate the efficacy of nucleosides as a prophylactic agent against reactivation of hepatitis B virus (HBV) in HBsAg-positive patients with non-hepatic tumors after chemotherapy.. Fifty-eight patients with non-hepatic tumors were divided into prevention group and control group. The patients of prevention group received nucleosides as a prophylactic agent before chemotherapy and were compared with the control ones about the clinical manifestation of HBV reactivation. Then, the patients of the control group were divided into three groups according to antiviral drugs, use or not and time of the use. The patients having HBV reactivation but never received nucleosides were included in the group A, the patients receiving nucleosides after having HBV reactivation were divided into the group B, and the patients receiving nucleosides before HBV reactivation were divided into the group C. The progression, prognosis and curative effect among the three groups were compared.. The rate of HBV reactivation, incidence of severe hepatitis, mortality rate of the control group (61.1%, 27.8%, 16.7%) were significantly higher than those of the prevention group (13.6%, 0, 0), and liver dysfunction was more serious than that in the prevention group. In the control group, all the 5 patients of group A died of liver failure. Of the 13 patients in the group B, 4 cases suffered from severe hepatitis and 1 of them died of the disease. Of the 18 patients in the group C, 4 cases suffered from HBV reactivation, but the clinical manifestation was milder than that of the group B.. Nucleosides can be used as a prophylactic measure to prevent HBV reactivation. If chemotherapy had begun, the use of nucleosides may reduce the risk of HBV reactivation. Even if patients had suffered from HBV reactivation, the use of nucleosides may still help the recovery of liver function and improve prognosis.

Topics: Adult; Antineoplastic Agents; Antiviral Agents; Breast Neoplasms; Female; Follow-Up Studies; Guanine; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Lamivudine; Lung Neoplasms; Lymphoma; Male; Middle Aged; Nucleosides; Pyrimidinones; Retrospective Studies; Telbivudine; Thymidine; Virus Activation

Topics: Adolescent; Adult; Animals; Bleomycin; Bone Marrow; Bone Marrow Transplantation; Cell Separation; Child; Child, Preschool; Clinical Trials as Topic; Cyclophosphamide; Drug Evaluation; Etoposide; Graft vs Host Disease; Hematopoietic Stem Cells; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Lysophosphatidylcholines; Methylprednisolone; Neoplasms, Experimental; Phospholipid Ethers; Pyrimidinones; Transplantation, Autologous; Transplantation, Isogeneic

Monocarboxylate transporters (MCT) modulate tumor cell metabolism and offer promising therapeutic targets for cancer treatment. Understanding the impact of MCT blockade on tumor cell metabolism may help develop combination strategies or identify pharmacodynamic biomarkers to support the clinical development of MCT inhibitors now in clinical trials. In this study, we assessed the impact of the MCT1 inhibitor AZD3965 on cancer cell metabolism

Topics: Acrylates; Animals; Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; Cell Line, Tumor; Energy Metabolism; Female; HT29 Cells; Humans; Lactic Acid; Lymphoma; Magnetic Resonance Spectroscopy; Metformin; Mice, SCID; Mitochondria; Monocarboxylic Acid Transporters; Muscle Proteins; Pyrimidinones; Symporters; Thiophenes; Xenograft Model Antitumor Assays

During apoptosis, physical changes in the plasma membrane prepare the cell for clearance by phagocytes and hydrolysis by secretory phospholipase A(2) (sPLA(2)). The relationships among these changes have not been adequately established, especially for hormone-stimulated apoptosis. This study addresses these issues for glucocorticoid-induced apoptosis in S49 lymphoma cells. Flow cytometry, microscopy, and fluorescence spectroscopy were used to assess merocyanine 540 emission, laurdan generalized polarization, phosphatidylserine exposure, caspase activation, and membrane permeability to propidium iodide in the absence and presence of sPLA(2). The earliest event observed was activation of cellular caspases. Results with membrane probes suggest that interlipid spacing also increases early during apoptosis and precedes transbilayer migration of phosphatidylserine, DNA fragmentation, and a general increase in lipid order associated with blebbing and dissolution of the cells. The activity of sPLA(2) appeared to be linked more to lipid spacing than to loss of membrane asymmetry. The early nature of some of these events and their ability to promote activity of a proinflammatory enzyme suggests the possibility of an inflammatory response during T-lymphocyte apoptosis.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Membrane; Cell Survival; Enzymes; Flow Cytometry; Fluorescent Dyes; Glucocorticoids; Hydrolysis; Lipid Metabolism; Lymphoma; Microscopy; Phosphatidylserines; Phospholipases A2; Pyrimidinones; Spectrometry, Fluorescence; Time Factors; Water

Lopinavir, an antiretroviral drug against human immunodeficiency virus (HIV), was administered through various routes to an HIV-infected patient with duodenal malignant lymphoma. Antiretroviral drugs were first administered through a jejunal tube, and then through bypass route between the stomach and jejunum that was 20 cm distal from the ligament of Treitz after surgery. Oral administration through the bypass achieved sufficient serum concentrations of lopinavir, whereas administration through the jejunal tube did not.

Topics: Administration, Oral; Adult; Anti-Retroviral Agents; Duodenal Neoplasms; Gastric Bypass; HIV Infections; Humans; Intestinal Absorption; Jejunum; Lopinavir; Lymphoma; Male; Pyrimidinones

Merocyanine 540 (MC 540) is a photosensitizing dye that has been used in a phase I clinical trial for the purging of leukemia and lymphoma cells from autologous bone marrow grafts. In this paper we examine the role of plasma membrane negative charge, plasma membrane fluidity, and plasma membrane hydrophobicity in the regulation of a cell's susceptibility to MC 540-sensitized photoirradiation. Among solid tumor cells, we found an inverse correlation between surface electronegativity, affinity for dye molecules, and susceptibility to MC 540-sensitized photoinactivation. That is, the least electronegative cells bound the highest amount of dye and were the most susceptible to dye-sensitized photoirradiation. By contrast, no such correlations were found among leukemia/lymphoma cells. This suggested that dye binding and susceptibility to MC 540-mediated photodynamic damages are regulated differently in hematopoietic/lymphopoietic and solid tumor cells.

Topics: Bone Marrow; Bone Marrow Cells; Cell Membrane; Cell Separation; Humans; Leukemia; Light; Lymphoma; Membrane Fluidity; Neoplasms; Neuraminidase; Pyrimidinones; Radiation-Sensitizing Agents; Solubility; Surface Properties; Trypsin; Tumor Cells, Cultured

The potential of various photoradiation therapy for the in vitro purging of residual tumor cells from autologous bone marrow (BM) transplants is discussed in this paper. The results with fluorescent dyes, Dihematoporphyrin Ether (DHE) and Merocyanine-540 (MC-540) are detailed. Following photoradiation of cells with white light, both DHE and MC-540 showed high cytocidal activity towards lymphoid and myeloid neoplastic cells, but had significantly less effect on normal granulocyte-macrophage (CFU-GM), erythroid (BFU-E) and mixed colony-forming (CFU-GEMM) progenitor cells. Acute promyelocytic leukemia (HL-60), non-B, non-T, cALLa positive acute lymphoblastic leukemia (Reh), and diffuse histiocytic B-cell lymphoma (SK-DHL-2) cell lines were exposed to different drug concentrations in combination with white light at a constant illumination rate of 50,000 lux. With DHE doses varying from 2.0 to 2.5 ug/ml and MC-540 concentrations of 15 to 20 ug/ml, clonogenic tumor cells could be reduced by more than 4 logs, when treated alone or in mixtures with normal irradiated human marrow cells. However, preferential cytotoxicity towards neoplastic cells was highly dependent on the mode of light activation. MC-540 had no substantial effect on malignant lymphoid (SK-DHL-2) and myeloid (HL-60) cells, and on normal marrow myeloid (CFU-GM) precursors, when the drug incubation was performed in the dark and followed by light exposure of washed cells. Equal doses of MC-540 (15-20 ug/ml) could preferentially eliminate tumor cells under conditions of simultaneous light and drug treatment (30 minutes at 37 degrees C). Using DHE (2.5 ug/ml), 29.3%, 46.8%, and 27.5% of normal marrow CFU-GM, BFU-E, and CFU-GEMM, respectively, were spared, following sequential drug and light exposure of cells, while simultaneous treatment reduced both normal (CFU-GM) and neoplastic cells below the limits of detection. The data from various centers is briefly discussed with special emphasis on clinical trials. Our results provide a useful model for leukemia and lymphoma cells and suggest that these phototherapy experiments can be implemented into clinical trials.

Topics: Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cell Survival; Colony-Forming Units Assay; Dihematoporphyrin Ether; Hematoporphyrins; Humans; Leukemia, Lymphoid; Leukemia, Promyelocytic, Acute; Lymphoma; Photochemotherapy; Pyrimidinones; Radiation-Sensitizing Agents; Transplantation, Autologous; Tumor Cells, Cultured

Several guanosine analogues were synthesized in the pyrazolo[3,4-d]pyrimidine ring system with various substituents at the 3-position. The new analogues prepared here include the CH3 (2-amino-3-methyl-1-beta-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4 (5H)-one, 13a), the phenyl (2-amino-3-phenyl-1-beta-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4 (5H)-one, 13b), and the NH2 (3,6-diamino-1-beta-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)- one, 17) substituted derivatives. These new agents, as well as several other 3-substituted derivatives including H, Br, OCH3, COOH, and oxo, were evaluated for their ability to potentiate certain murine immune functions relative to the known active agent 5-amino-3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H) -dione (4, 7-thia-8-oxoguanosine). The biological evaluation included the (1) ex vivo determination of increased natural killer cell function and (2) in vivo antiviral protection against a lethal challenge of Semliki Forest virus. The 3-unsubstituted (5a) and the 3-bromo (5c) derivatives were found to be the most active immunopotentiators in this series.

Topics: Adjuvants, Immunologic; Animals; Chemical Phenomena; Chemistry; Cytotoxicity, Immunologic; Guanosine; Killer Cells, Natural; Lymphoma; Mice; Molecular Structure; Pyrazoles; Pyrimidinones; Semliki forest virus; T-Lymphocytes; Togaviridae Infections

To assess the potential of photoradiation therapy for the in vitro purging of residual tumor cells from autologous bone marrow (BM) transplants, we studied normal marrow and tumor cell clonogenicity in response to different light-activated compounds by using the fluorescent dyes dihematoporphyrin ether (DHE) and merocyanine-540 (MC-540). After photoradiation of cells with white light, both DHE and MC-540 showed high cytocidal activity toward lymphoid and myeloid neoplastic cells but had a significantly lesser effect on normal granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and mixed colony-forming (CFU-GEMM) progenitor cells. Acute promyelocytic leukemia (HL-60), non-B, non-T, CALLA-positive acute lymphoblastic leukemia (Reh), and diffuse histocytic B cell lymphoma (SK-DHL-2) cell lines were exposed to different drug concentrations in combination with white light at a constant illumination rate of 50,000 lux. With DHE doses varying from 2.0 to 2.5 micrograms/mL and MC-540 concentrations of 15 to 20 micrograms/mL, clonogenic tumor cells could be reduced by more than 4 logs when treated alone or in mixtures with normal irradiated human marrow cells. However, preferential cytotoxicity towards neoplastic cells was highly dependent on the mode of light activation. MC-540 had no substantial effect on malignant lymphoid (SK-DHL-2) and myeloid (HL-60) cells and on normal marrow myeloid (CFU-GM) precursors when drug incubation was performed in the dark and followed by light exposure of washed cells. Equal doses of MC-540 (15 to 20 micrograms/mL) could preferentially eliminate tumor cells under conditions of simultaneous light and drug treatment (30 minutes at 37 degrees C). When using DHE (2.5 micrograms/mL), 29.3%, 46.8%, and 27.5% of normal marrow CFU-GM, BFU-E, and CFU-GEMM, respectively, were spared after sequential drug and light exposure of cells, whereas simultaneous treatment reduced both normal (CFU-GM) and neoplastic cells below the limits of detection. In summary, our results indicate the usefulness of various photoradiation models for the ex vivo treatment of leukemic and lymphomatous bone marrow autografts.

Topics: Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cell Line; Dihematoporphyrin Ether; Hematopoietic Stem Cells; Hematoporphyrins; Humans; Leukemia; Lymphoma; Phototherapy; Pyrimidinones; Radiation-Sensitizing Agents; Transplantation, Autologous

Previous work based on fluorescence microscopic observation has indicated that leukemic leukocytes and immature hematopoietic precursor cells show a greater permeability to the membrane stain, merocyanine 540 (MC) than normal, mature cells and that changes in MC permeability seem to be correlated with failure in membrane maturation during leukemic cell differentiation. In the interest of addressing questions concerning the efficacy of the MC staining reaction as a diagnostic tool in clinical contexts relevant to leukemia, we have looked for any correlations which might exist between the MC staining patterns displayed by circulating leukocytes, cellular morphology and the clinical status of 53 patients with leukemia and non-Hodgkin's lymphoma, using fluorescence activated cell sorting. In 85% of cases, MC staining was found to be correlated with blood status while in 15% of the cases discrepancies were found. These results are discussed in light of changes in the hematologic profiles of the patients during the clinical course.

Topics: Diagnosis, Differential; Diagnostic Errors; Humans; Leukemia; Leukocytes; Lymphoma; Microscopy, Fluorescence; Neoplasm Staging; Pyrimidinones; Staining and Labeling

Topics: Adenosine; Animals; Ascitic Fluid; Aza Compounds; Biological Transport; Bromodeoxyuridine; Carbon Isotopes; Cell Division; Cell-Free System; Cells, Cultured; Guanosine; Inosine; Lymphoma; Male; Mercaptopurine; Methotrexate; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Pyrazoles; Pyrimidinones; Pyrroles; Ribonucleosides; Thymidine; Time Factors; Transplantation, Homologous