chiniofon and Neoplasms

In this review, the recent synthetic approaches of amino hexahydroquinolines and their spirocyclic structures were highlighted. The synthetic routes include, two-components, three-components or fourcomponents reactions. The two-component [3+3] atom combination reaction represents the simplest method. It involves Michael addition of the electron rich β-carbon of β-enaminones to the activated double bond of cinnamonitriles followed by cyclization to yield hexahydroquinoline compounds. The bioactivity profiles and SAR studies of these compounds were also reviewed with emphasis to the utility of these substances as antimicrobial, anticancer and antitubercular agents, as well as calcium channel modulators.

Topics: Anti-Bacterial Agents; Antineoplastic Agents; Bacteria; Dose-Response Relationship, Drug; Humans; Hydroxyquinolines; Neoplasms; Spiro Compounds; Structure-Activity Relationship

The proteasome is an intracellular enzyme complex that degrades ubiquitin-tagged proteins and thereby regulates protein levels within the cell. Given this important role in maintaining cellular homeostasis, it is perhaps somewhat surprising that proteasome inhibitors have a therapeutic window. Proteasome inhibitors have demonstrated clinical efficacy in the treatment of multiple myeloma and mantle cell lymphoma and are under evaluation for the treatment of other malignancies. Bortezomib is the first and only Food and Drug Administration-approved proteasome inhibitor that inhibits this enzyme complex in a reversible fashion. Although bortezomib improves clinical outcomes when used as a single agent, most patients do not respond to this drug and those who do respond almost uniformly relapse. As such, efforts are underway to develop proteasome inhibitors that act through mechanisms distinct from that of bortezomib. Specifically, inhibitors that bind the active site of the proteasome and inhibit the complex irreversibly have been developed and are in advanced clinical trials. Inhibitors that act on sites of the proteasome outside of the catalytic center have also been identified and are in preclinical development. In this review, we discuss the structure and function of the proteasome. We then focus on the molecular biology, chemistry, and the preclinical and clinical efficacy of novel proteasome inhibitors as strategies to inhibit this target and overcome some forms of bortezomib resistance.

Topics: Allosteric Site; Animals; Antineoplastic Agents; Apoptosis; Boronic Acids; Bortezomib; Cell Line, Tumor; Chloroquine; Clioquinol; Drug Resistance, Neoplasm; Humans; Hydroxyquinolines; Lactones; Neoplasms; Oligopeptides; Protease Inhibitors; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines; Pyrroles; Threonine; Ubiquitinated Proteins; Ubiquitination

Topics: 1-Propanol; 2,4-Dichlorophenoxyacetic Acid; 2,4,5-Trichlorophenoxyacetic Acid; Alkenes; Animals; Carcinogens, Environmental; Chemical Industry; Coloring Agents; Dioxanes; Dioxins; Environmental Pollutants; Ethylene Dibromide; Ethylene Glycols; Fumigation; Humans; Hydroxyquinolines; Iodides; Neoplasms; Neoplasms, Experimental; Phenols; Phosphoric Acids; Propane; Quinones; Risk; Succinates; Xylenes

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

Twelve new complexes

Topics: Antineoplastic Agents; Autophagy; Cell Line, Tumor; Copper; Glutathione; Humans; Hydrogen Peroxide; Hydroxyquinolines; Neoplasms; Quinolines; Schiff Bases

Anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibodies are currently used in the clinic to interupt the PD-1/PD-L1 immune checkpoint, which reverses T cell dysfunction/exhaustion and shows success in treating cancer. Here, we report a histone demethylase inhibitor, 5-carboxy-8-hydroxyquinoline (IOX1), which inhibits tumour histone demethylase Jumonji domain-containing 1A (JMJD1A) and thus downregulates its downstream β-catenin and subsequent PD-L1, providing an antibody-independent paradigm interrupting the PD-1/PD-L1 checkpoint. Synergistically, IOX1 inhibits cancer cells' P-glycoproteins (P-gp) through the JMJD1A/β-catenin/P-gp pathway and greatly enhances doxorubicin (DOX)-induced immune-stimulatory immunogenic cell death. As a result, the IOX1 and DOX combination greatly promotes T cell infiltration and activity and significantly reduces tumour immunosuppressive factors. Their liposomal combination reduces the growth of various murine tumours, including subcutaneous, orthotopic, and lung metastasis tumours, and offers a long-term immunological memory function against tumour rechallenging. This work provides a small molecule-based potent cancer chemo-immunotherapy.

Topics: Animals; Antibodies; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Cell Line, Tumor; Cell Survival; Doxorubicin; HCT116 Cells; Humans; Hydroxyquinolines; Immunotherapy; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Neoplasms, Experimental; NIH 3T3 Cells; Programmed Cell Death 1 Receptor; T-Lymphocytes; Tumor Burden

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

Chemotherapy-induced alopecia has been well documented as a cause of distress to patients undergoing cancer treatment. Almost all traditional chemotherapeutic agents cause severe alopecia. Despite advances in the treatment of chemotherapy-induced alopecia, there is no effective treatment for preventing chemotherapy-induced alopecia.. In the present study, we investigated the potential role of a multi-target iron chelator, M30 in protecting against cyclophosphamide-induced alopecia in C57BL/6 mice implanted with an osmotic pump. M30 enhanced hair growth and prevented cyclophosphamide-induced abnormal hair in the mice. Furthermore, we examined the gene expression profiles derived from skin biopsy specimens of normal mice, cyclophosphamide-treated mice, and cyclophosphamide treated mice with M30 supplement.. The top genes namely Tnfrsf19, Ercc2, Lama5, Ctsl, and Per1 were identified by microarray analysis. These genes were found to be involved in the biological processes of hair cycle, hair cycle phase, hair cycle process, hair follicle development, hair follicle maturation, hair follicle morphogenesis, regulation of hair cycle.. Our study demonstrates that M30 treatment is a promising therapy for cyclophosphamide-induced alopecia and suggests that the top five genes have unique preventive effects in cyclophosphamide-induced transformation.

Topics: Alopecia; Animals; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Cyclophosphamide; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; Humans; Hydroxyquinolines; Induction Chemotherapy; Mice; Mice, Inbred C57BL; Microarray Analysis; Neoplasms; Receptors, Tumor Necrosis Factor

The effort was taken to develop a series of benzothiazole and quinoline fused bioactive compounds obtained through a four-step synthetic route using a range of substituted acetoacetanilides. Achieved N-(benzo[d]thiazol-2-yl)-2-hydroxyquinoline-4-carboxamides (6a-l) were produced up to 96% of yield while the eco-friendly p-TSA used as a catalyst. Further, the anticancer activity of these compounds was determined using a range of cancer cell lines starting from MCF-7 (Breast cancer), HCT-116 (Colon cancer), PC-3 & LNCaP (Prostate) and SK-HEP-1 (Liver cancer). Present study compounds were also testified for antioxidant properties prior to anticancer studies since the Reactive Oxygen Species (ROS) being vital in cancer development. To determine the cell membrane stability effects of the compounds, human red blood cells (HRBC) based membrane protection assay was determined. In the results, compounds 6a-l were able to produce a dominated result values over PC3 cell lines (Prostate cancer) than the other cell lines used in this study. Since the connectivity of human germ cell alkaline phosphatase (hGC-ALP) in the development of prostate cancer is known, the most active compounds were evaluated for the hGC-ALP inhibition in order to ensure a mechanism of anticancer action of these compounds. The mode of interaction and binding affinity of these compounds was also investigated by a molecular docking study. In the results, 6d, 6i, 6k, and 6l were found with least IC

Topics: Alkaline Phosphatase; Antineoplastic Agents; Cell Proliferation; Drug Discovery; High-Throughput Screening Assays; Humans; Hydroxyquinolines; Molecular Structure; Neoplasms; Quinolines; Signal Transduction; Structure-Activity Relationship; Tumor Cells, Cultured

8-Hydroxyquinolines (HQ), including clioquinol, possess cytotoxic properties and are widely used as ligands for metal-based anticancer drug research. The number and identity of substituents on the HQ can have a profound effect on activity for a variety of inorganic compounds. Ruthenium complexes of HQ exhibit radically improved potencies, and operate by a new, currently unknown, mechanism of action. To define structure-activity relationships (SAR), a family of 22 Ru(II) coordination complexes containing mono-, di- and tri-substituted hydroxyquinoline ligands were synthesized and their biological activity evaluated. The complexes exhibited promising cytotoxic activity against a cancer cell line, and the SAR data revealed the 2- and 7-positions as key sites for the incorporation of halogens to improve potency. The Ru(II) complexes potently inhibited translation, as demonstrated by an in-cell translation assay. The effects were seen at 2-15-fold higher concentrations than those required to observe cytotoxicity, suggesting that prevention of protein synthesis may be a primary, but not the exclusive mechanism for the observed cytotoxic activity.

Topics: Antineoplastic Agents; Cell Line, Tumor; Coordination Complexes; Humans; Hydroxyquinolines; Ligands; Models, Molecular; Neoplasms; Protein Biosynthesis; Ruthenium; Structure-Activity Relationship; Transcription, Genetic

Proliferation and programmed cell death are tightly correlated with the ubiquitin-proteasome system (UPS). Alterations in the UPS may be implicated in pathological conditions such as the proteasome over-activity in cancer cells. Mounting evidence indicates that many types of actively proliferating malignant cells are more sensitive to proteasome inhibition than normal cells, and therefore UPS inhibitors are actively pursued as anticancer agents. The approval of the proteasome inhibitor drug bortezomib for the treatment of myeloma and lymphoma further highlights the need for UPS inhibitors. Recent studies have suggested that clioquinol and 5-amino-8-hydroxyquinoline can inhibit proteasome activity and induce apoptosis in human cancer cells. As for clioquinol, a copper-dependent and -independent mechanism has been proposed to explain the inhibition of the proteasome whereas the activity of 5-amino-8-hydroxyquinoline has not been explored in the presence of copper(ii) ions. Herein, we investigated the biological activity of some 8-hydroxyquinolines by using human ovarian (A2780) and lung (A549) cancer cells. The effect of copper(ii) on the activity of these compounds was also evaluated. The investigated systems inhibit the chymotrypsin-like activity of the proteasome and induce growth inhibition and apoptosis in a concentration-dependent manner. Copper(ii) ions increase the activity of 8-hydroxyquinoline derivatives except in the case of 5-amino-8-hydroxyquinoline. This study suggests the great potential of amino- and chloro-8-hydroxyquinolines as anticancer agents. Furthermore, it clarifies some aspects concerning the activity of 5-amino-8-hydroxyquinoline, which has been previously proposed as a proteasome inhibitor capable of overcoming resistance to bortezomib.

Topics: Antineoplastic Agents; Cell Proliferation; Copper; Female; Humans; Hydroxyquinolines; Neoplasms; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Tumor Cells, Cultured; Ubiquitination

Topics: Antineoplastic Agents; Blotting, Western; Cell Cycle; Cell Proliferation; Coordination Complexes; Copper; Crystallography, X-Ray; Humans; Hydroxyquinolines; Ligands; Models, Molecular; Molecular Structure; Neoplasms; Reactive Oxygen Species; Thiosemicarbazones

Drug resistance is a common cause of treatment failure in cancer patients and encompasses a multitude of different mechanisms. The aim of the present study was to identify drugs effective on multidrug resistant cells.. The RPMI 8226 myeloma cell line and its multidrug resistant subline 8226/Dox40 was screened for cytotoxicity in response to 3,000 chemically diverse compounds using a fluorometric cytotoxicity assay (FMCA). Follow-up profiling was subsequently performed using various cellular and biochemical assays.. One compound, designated VLX40, demonstrated a higher activity against 8226/Dox40 cells compared to its parental counterpart. VLX40 induced delayed cell death with apoptotic features. Mechanistic exploration was performed using gene expression analysis of drug exposed tumor cells to generate a drug-specific signature. Strong connections to tubulin inhibitors and microtubule cytoskeleton were retrieved. The mechanistic hypothesis of VLX40 acting as a tubulin inhibitor was confirmed by direct measurements of interaction with tubulin polymerization using a biochemical assay and supported by demonstration of G2/M cell cycle arrest. When tested against a broad panel of primary cultures of patient tumor cells (PCPTC) representing different forms of leukemia and solid tumors, VLX40 displayed high activity against both myeloid and lymphoid leukemias in contrast to the reference compound vincristine to which myeloid blast cells are often insensitive. Significant in vivo activity was confirmed in myeloid U-937 cells implanted subcutaneously in mice using the hollow fiber model.. The results indicate that VLX40 may be a useful prototype for development of novel tubulin active agents that are insensitive to common mechanisms of cancer drug resistance.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Flow Cytometry; Hydroxyquinolines; Inhibitory Concentration 50; Mice; Neoplasms; Oligonucleotide Array Sequence Analysis; Tubulin

8-Hydroxyquinoline derivatives are metal-binding compounds that have recently attracted interest as therapeutic agents for cancer therapy. In this scenario, we designed and synthesized three new glucoconjugates, 5,7-dichloro-8-quinolinyl-β-D-glucopyranoside, 5-chloro-8-quinolinyl-β-D-glucopyranoside and 2-methyl-8-quinolinyl-β-D-glucopyranoside and investigated their biological properties in comparison to the parent 8-hydroxyquinoline derivatives in the presence of Cu(2+). In vitro data show that 2 out of 3 glycosylated compounds possess a pharmacologically-relevant antiproliferative activity against tumor cells, similar to that of their parent compounds; this activity is associated with a relevant triggering of apoptosis. The pharmacological profile of the glucoconjugates depends on the cellular enzymatic β-glucosidase activity, as demonstrated by the inhibition of antiproliferative activity in the presence of the 2,5-dideoxy-2,5-imino-D-mannitol.

Topics: Antineoplastic Agents; Apoptosis; beta-Glucosidase; Binding Sites; Caco-2 Cells; Catalytic Domain; Cell Line, Tumor; Coordination Complexes; Copper; Enzyme Activation; Glycosylation; Humans; Hydroxyquinolines; Ionophores; Molecular Docking Simulation; Neoplasms; Prodrugs; Protein Stability

Protein kinases catalyze protein phosphorylation and thereby control the flow of information through signaling cascades. Currently available methods for concomitant assessment of the enzymatic activities of multiple kinases in complex biological samples rely on indirect proxies for enzymatic activity, such as posttranslational modifications to protein kinases. Our laboratories have recently described a method for directly quantifying the enzymatic activity of kinases in unfractionated cell lysates using substrates containing a phosphorylation-sensitive unnatural amino acid termed CSox, which can be monitored using fluorescence. Here, we demonstrate the utility of this method using a probe set encompassing p38α, MK2, ERK1/2, Akt, and PKA. This panel of chemosensors provides activity measurements of individual kinases in a model of skeletal muscle differentiation and can be readily used to generate individualized kinase activity profiles for tissue samples from clinical cancer patients.

Topics: Animals; Cell Differentiation; Cell Line; HeLa Cells; Hep G2 Cells; HT29 Cells; Humans; Hydroxyquinolines; Kinetics; Mice; Muscle, Skeletal; Neoplasms; Phosphorylation; Protein Kinases; Signal Transduction; Substrate Specificity; Sulfonamides

3-Aryl-2-quinolone derivates were extensively investigated for their inhibition of farnesyl transferase. Taking this as a cue, we studied the other possible mechanism of antitumor activity of 2-quinolone derivates. A series of new 2-quinolone derivatives have been synthesized and screened for their cytotoxicity by trypan blue assay on Ehrlich ascites carcinoma cells and MTT assay on MCF-7 cells. Compound 1a (nJST) was found to be more effective in both studies with the lowest CTC(50) value among all nine synthesized compounds. This compound was further screened on four different cell lines, viz. human breast adenocarcinoma (MCF-7, MDA-MB-231), colon cancer (HCT-15), murine melanoma (B16F10) cell lines for 24 and 48 h. The CTC(50) value of the compound was found to be <10 μm. Compound 1a induced DNA damage which was revealed by DNA fragmentation studies and further confirmed by nuclear staining. The compound also showed significant elevation in Bax and reduction Bcl-2 gene expression levels. Acute toxicity study in mice indicated that the compound is safe till 2000 mg/kg. Two different doses 50 and 100 mg/kg were selected and studied in Ehrlich ascites carcinoma model of cancer and have shown significant improvement in survival time and hematological parameters.

Topics: Animals; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Carcinoma, Ehrlich Tumor; Cell Line, Tumor; Cell Survival; DNA Fragmentation; Female; Gene Expression Regulation, Neoplastic; Humans; Hydroxyquinolines; Mice; Neoplasms; Quinolones

Selective acylation of the phenolic hydroxyl group of 10-hydroxycamptothecin has been accomplished using phenyl dichlorophosphate. Additional modification of the 10-OH as an ether permits a 20-acyl derivative to be synthesized. This result along with data from a 6-hydroxyquinoline model strongly suggests that powerful intermolecular hydrogen bonding exists in the parent molecule.

Topics: Acylation; Animals; Antineoplastic Agents; Camptothecin; Carboxylic Acids; Hydrogen Bonding; Hydroxyquinolines; Indicators and Reagents; Leukemia P388; Magnetic Resonance Spectroscopy; Neoplasms; Polyethylene Glycols; Rats; Tumor Cells, Cultured

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

Some types of cancer cells have high levels of beta-glucuronidase activity. This enzyme is able to deglucuronidate a variety of glucuronide derivatives on the cell membrane. Either O- or N-glucuronides can be selectively incorporated into the cancer cells. If the aglycone is cytotoxic, the glucuronide can potentially be used as a selective anti-cancer drug in cancers with high levels of beta-glucuronidase activity. Nevertheless, in vitro studies carried out by various investigators have shown that the cytotoxicities of several glucuronides in cancer cells are not sufficiently high for their use as effective anti-cancer drugs. For this reason, we have synthesized glucuronide compounds radiolabelled with iodine-125 combining the radiotoxicity of this Auger electron emitter with the chemotoxicity of the aglycone portion of the glucuronide.

Topics: Animals; Antineoplastic Agents; Combined Modality Therapy; Glucuronates; Glucuronidase; Humans; Hydroxyquinolines; Iodine Radioisotopes; Magnetic Resonance Spectroscopy; Methods; Neoplasms; Rabbits

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

A simultaneous investigation of platelet regeneration time (PRT) based upon malondialdehyde (MDA) recovery after a single oral intake of 500 mg of aspirin and of platelet survival time (PST) after labelling with 51chromium or 111indium oxine was performed in 25 cancerous patients. A pilot study conducted with 9 healthy volunteers demonstrated that the MDA assay was highly reproducible and specific for the platelet cycloxygenase activity. The pattern of MDA recovery after aspirin ingestion was linear in the healthy volunteers and in the patients presenting both a normal and an accelerated platelet turnover. PST were calculated using the four mathematical models recommended by the International Committee for Standardization in Hematology; the best fit was given by the multiple hit model in 22 cases and by the linear regression model in 3 cases. The mean results obtained in the patients investigated with the 51chromium were consistently shorter than those obtained in the patients investigated with the 111indium oxine while the mean PRT were almost identical in the two groups. An excellent correlation between PRT and PST was observed after 111indium oxine labelling and using the weighted mean method for PST determination. These results suggest that the 111indium oxine technique is a better method for platelet labelling and that the results provided by the weighted mean method reflect more closely the in vivo platelet turnover than those provided by the multiple hit model.

Topics: Adult; Aspirin; Blood Platelets; Cell Survival; Chromium Radioisotopes; Female; Humans; Hydroxyquinolines; Indium; Isotope Labeling; Male; Malondialdehyde; Neoplasms; Organometallic Compounds; Oxyquinoline; Radioisotopes; Time Factors

At least one microCi of 111indium oxine (111InOx) could be incorporated into 10(6) human tumor cells without cytotoxicity as determined by colony assay or by trypan blue staining. 111In bound to prekilled cells was removed preferentially by washings, and prelabeled cells killed with diphtheria toxin released radioactivity much more rapidly than did viable cells. The metal chelator calcium disodium edetate did not facilitate 111In removal from either viable or dead cells. High sensitivity can be obtained for in vitro or in vivo cytotoxicity assays using human cells prelabeled with 111InOx.

Topics: Animals; Cell Line; Cell Survival; Deoxyuridine; Diphtheria Toxin; Edetic Acid; Half-Life; Humans; Hydroxyquinolines; Indium; Iodine Radioisotopes; Isotope Labeling; Mice; Mice, Nude; Neoplasms; Organometallic Compounds; Oxyquinoline; Radioisotopes

One hundred twenty-nine 111In-oxine-labeled leukocyte scintiscans have been performed in 117 patients with cancer in order to diagnose localized infectious disease. Of the 115 contributive scans, 40 were in patients with localizing signs, whereas in 75 fever of unknown origin constituted the indication for this examination. The overall specificity of the method was 95.4%, the overall sensitivity 86%, and the global accuracy 91.3%. In 10 cases with localizing signs, the 111In-oxine granulocyte scintigram allowed exclusion of the diagnosis of infection, whereas in 17 instances without localizing signs, a focal infectious process was demonstrated. Heterologous donor leukocytes were used successfully in five instances. With the exception of accumulation of label at the site of an osteolytic metastasis in one case, no uptake was observed in primary or secondary tumors. It is concluded that 111In-oxine-labeled leukocytes constitute a valuable tool in the diagnosis and localization of infection in patients with malignant disease.

Topics: Bacterial Infections; Bone Neoplasms; Diagnosis, Differential; False Negative Reactions; Female; Humans; Hydroxyquinolines; Indium; Leukemia, Lymphoid; Leukocytes; Liver Neoplasms; Lymphoma; Neoplasms; Organometallic Compounds; Oxyquinoline; Radioisotopes; Radionuclide Imaging; Rectal Neoplasms; Uterine Cervical Neoplasms

Topics: Bismuth; Cardiovascular Diseases; Diazepam; Drug Therapy; Endocrine System Diseases; Gastrointestinal Diseases; Glafenine; Hepatitis; Humans; Hydroxyquinolines; Hypersensitivity; Infections; Kidney Diseases; Metabolic Diseases; Neoplasms; Nervous System Diseases; Practolol; Respiratory Tract Diseases; Rheumatic Diseases