roquinimex and Neoplasms

Roquinimex (Linomide) has been demonstrated to suppress tumor growth in animal models. The effect is at least in part related to enhanced numbers and activity of natural killer (NK) cells. In this clinical pilot study, roquinimex was given at increasing doses (0.05 mg/kg to 0.6 mg/kg) to 13 patients (performance status 0-3) with various malignant disorders. Immunology parameters were followed and side effects were observed during the study. The plasma pharmacokinetics of roquinimex was studied at the 0.2 mg/kg dose level. The clinical side effects were dominated by musculoskeletal discomfort, nausea, and pain. No significant hematological or biochemical toxicity was observed. Pharmacokinetic analysis at the 0.2 mg/kg dose level revealed a Cmax of 4.0 mumol/L at tmax of 1.2 hr and an elimination half-life of 42 hr. Increased numbers of phenotypic NK cells, activated T (DR+CD4+) cells, and monocytes were observed after administration of roquinimex compared with pretreatment values. Roquinimex seems to be an active immunomodulator with manageable toxicity. Further exploration of therapeutic efficacy is warranted.

Topics: Adjuvants, Immunologic; Adult; Aged; Antineoplastic Agents; Female; Humans; Hydroxyquinolines; Killer Cells, Natural; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Pilot Projects; T-Lymphocytes

According to WHO, in 2017, about 90.5 million people suffered from cancer and about 8.8 million deaths occurred due to disease. Although the chemotherapeutic agents have decreased the mortality among the cancer patients but high toxicity and non-specific targets are still major drawbacks. Many researchers have identified linomide, a 4-hydroxy-2-quinolone derivative, as a lead molecule for the development of anticancer agents. With this background, we thought of the following objective.. The objective of this research work involves the synthesis of a series of N-(2-(4- hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)-2-oxoethyl)-N-alkyl substituted benzene sulfonamides IVa-d (1-3) by replacing the anilide moiety at the third position of linomide with sulfamoylacyl and also N-methyl by N-phenyl functionality. To perform in silico anticancer activity by using Molegro Virtual Docker (MVD-2013, 6.0) software and in vitro anticancer activity by MTT assay.. The starting material 4-hydroxy-1-phenylquinolin-2(1H)-one was treated with N-bromosuccinamide to yield compound II. Condensation of compound II with primary amines resulted in compounds IIIa-d, which, on coupling with substituted aromatic sulfonyl chlorides yield the title compounds IVa-d (1-3).. All the synthesized compounds were satisfactorily characterized by spectral data. The results of docking revealed that the synthesized compounds exhibited well-conserved hydrogen bonds with one or more amino acid residues in the active pocket of EGFRK tyrosine kinase domain (PDB ID: 1m17). The MolDock Score of compound IVd-1 (-115.503) was the highest amongst those tested. The in vitro anticancer activity results showed that compound IVc-1 (R= - (CH2) 2-CH3 ; R'= -H) and IV d-1 (R= -CH2-C6H5; R'= -H) were found to be most potent against K562 cell line with an IC50 of 0.451 μM/ml and 0.455 μM/ml respectively. Compound IVd-1 also showed better potency against A549 cell line with IC50 value of 0.704 μM/ml.. The results of in silico and in vitro anticancer activity are in agreement with each other. Compound IV d-1 was found to be most active of the series.

Topics: A549 Cells; Antineoplastic Agents; Catalytic Domain; Cell Proliferation; Crystallography, X-Ray; Drug Design; Drug Screening Assays, Antitumor; ErbB Receptors; Humans; Hydrogen Bonding; Hydroxyquinolines; Inhibitory Concentration 50; K562 Cells; Molecular Docking Simulation; Neoplasms; Structure-Activity Relationship

Five years after the identification of the von Hippel-Lindau (VHL) gene, physicians, scientists and concerned VHL family members met to review the current state of knowledge on the diagnosis and treatment of VHL and to summarize the latest information on the biochemistry of the VHL protein (pVHL). The NIH and University of Pennsylvania groups reported the detection of germ-line mutations in 100% (93 of 93) of VHL families studied. Several studies determined the frequency of VHL germ-line mutations in individuals with a single manifestation of VHL without a family history of VHL. National groups to improve the diagnosis and treatment of individuals with VHL disease have been established in Great Britain, Denmark, France, Holland, Italy, Japan, Poland, and the United States. Evidence for the existence of genes that modify the expression of VHL was presented. The VHL protein appears to have several distinct functions: (a) down-regulation of hypoxia-inducible mRNAs; (b) proper assembly of the extracellular fibronectin matrix; (c) regulation of exit from the cell cycle; and (d) regulation of expression of carbonic anhydrases 9 and 12.

Topics: Animals; Carcinoma, Renal Cell; Central Nervous System Neoplasms; Cystadenoma, Papillary; Disease Models, Animal; DNA Mutational Analysis; Exons; Genes, Lethal; Genetic Testing; Genotype; Hemangioblastoma; Hemangioma; Humans; Hydroxyquinolines; Kidney Neoplasms; Ligases; Mice; Mice, Knockout; Mice, Nude; Neoplasms; Neovascularization, Pathologic; Nephrectomy; Pancreatic Neoplasms; Paraganglioma; Phenotype; Polymerase Chain Reaction; Proteins; Radiosurgery; Retinal Neoplasms; Trophoblasts; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases; von Hippel-Lindau Disease; Von Hippel-Lindau Tumor Suppressor Protein

LS 2616 (Linomide) is a new immunomodulator that enhances natural killer (NK)-cell activity, delayed-type hypersensitivity reaction, mitogen responsiveness of T cells, and antibody production. It suppresses tumor growth and reduces metastases in animal experiments. In a phase I clinical trial, the maximal tolerated dose will not necessarily be the maximally effective dose, so both effect and toxicity parameters have to be monitored. Because of the pleiotropic function of the drug, several biological responses have to be analyzed. Furthermore, different malignancies are associated with different immunologic disturbances both qualitatively and quantitatively, necessitating the use of normal controls and baseline assessments as well as a range of different malignancies. The pharmacokinetic features will differ from the kinetics of the biological responses, and thus both drug concentration and effect parameters will be followed over time. Repeated doses will give information needed for tailoring of optimal schedules for administration.

Topics: Adjuvants, Immunologic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation; Humans; Hydroxyquinolines; Neoplasms