ABSTRACT
Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.
Subject(s)
Humans , Anthraquinones , Chemistry , Pharmacology , Antineoplastic Agents , Chemistry , Pharmacology , Aziridines , Chemistry , Pharmacology , Cell Hypoxia , Indolequinones , Chemistry , Pharmacology , Molecular Structure , NAD(P)H Dehydrogenase (Quinone) , Chemistry , Pharmacology , Neoplasms , Drug Therapy , Pathology , Nitrogen Mustard Compounds , Chemistry , Pharmacology , Nitroimidazoles , Chemistry , Pharmacology , Phosphoramide Mustards , Chemistry , Pharmacology , Prodrugs , Chemistry , Pharmacology , Triazines , Chemistry , PharmacologyABSTRACT
This study is to evaluate the cytotoxicity of mitomycin C (MMC) and its analogue 5-(aziridin-1-yl)-3-hydroxymethyl-1-methylindole-4,7-dione (629) as well as the effect of transfection of constitutive androstane receptor (CAR) on their biological effects. HepG2 cells were transfected with the plasmids mCAR1/pCR3 mediated by liposome. Vector pCR3 was used as control. Transfected cells were screened by G418 resistance and limiting dilution. The expressions of plasmid mCAR1/pCR3 and CYP2B6 mRNA were detected by RT-PCR; Cytotoxicities of MMC and 629 in vitro were evaluated in g2car cells and HepG2 cells by MTT method under anaerobic and aerobic conditions. mRNA expression of CAR and CYP2B6 can not be detected in HepG2 cells and HepG2/pCR3 cells but can in g2car cells. It is shown that plasmid mCAR1/pCR3 was transfected into g2car cells successfully and target CYP2B6 was transactivated by CAR. To compare with aerobic and anaerobic, the cytotoxicities of MMC and 629 to HepG2 cells and g2car cells had significantly enhanced (P < 0.05), and transfect CAR gene can improve the cytotoxicity of MMC (P < 0.05), but not 629 (P > 0.05). Furthermore, CYP2B6 is one master enzyme for the metabolism of MMC and not 629. Transfection of CAR can increase expression of CYP2B6 mRNA in HepG2 cells, and can affect cytotoxicities of MMC and 629.
Subject(s)
Humans , Antibiotics, Antineoplastic , Pharmacology , Aryl Hydrocarbon Hydroxylases , Genetics , Aziridines , Pharmacology , Carcinoma, Hepatocellular , Metabolism , Pathology , Cell Death , Cell Hypoxia , Cell Line, Tumor , Cytochrome P-450 CYP2B6 , Indoles , Pharmacology , Inhibitory Concentration 50 , Liver Neoplasms , Metabolism , Pathology , Mitomycin , Pharmacology , Oxidoreductases, N-Demethylating , Genetics , Plasmids , RNA, Messenger , Metabolism , Receptors, Cytoplasmic and Nuclear , Genetics , Recombinant Proteins , Genetics , Transcription Factors , Genetics , TransfectionABSTRACT
Infectious bursal disease virus (IBDV) was inactivated by two different chemicals--formaldehyde and binary ethylenimine (BEI). Formaldehyde was used at 0.1% and 0.2%, while BEI was used at concentrations of 0.001 and 0.002 mol/L. These four vaccines were tested for their efficiency in generating humoral immune response in different groups of broiler chicks. Both BEI-inactivated vaccines gave relatively higher antibody titers and were almost twice as efficient as formaldehyde-inactivated ones.
Subject(s)
Animals , Antibodies, Viral , Blood , Aziridines , Pharmacology , Chickens , Formaldehyde , Pharmacology , Infectious bursal disease virus , Allergy and Immunology , Vaccination , Vaccines, Inactivated , Allergy and Immunology , Viral Vaccines , Allergy and ImmunologyABSTRACT
<p><b>AIM</b>To examine the effect of inducible nitric oxide synthase (iNOS) on tumour cells chemosensitivity to mitomycin C (MMC) analogue 5-aziridinyl-3-hydroxyl-1-methylindole-4,7-dione (629) in vitro, and elucidate the possible role of iNOS in the metabolism of 629.</p><p><b>METHODS</b>Human sarcoma cells (HT1080) and its iNOS gene transfected clones (iNOS9, iNOS12) were exposed to 629 at concentrations of 1 nmol x L(-1) - 100 micromol x L(-1). 3-[4, 5-Dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide (MTT) assay, agarose electrophoresis and flow cytometric analysis were used to determine cell sensitivity, deoxyribonucleic acid (DNA) damage and the change of cell cycle in above process, respectively. All experiments were performed both in air and under hypoxia parallelly.</p><p><b>RESULTS</b>629 was more toxic than MMC, and enhanced cytotoxicity under hypoxia, which resulted in cell necrosis. Sixteen hours after treated with 629, HT1080 cells and related iNOS-transfected clone cells were obviously blocked in G2/M phase.</p><p><b>CONCLUSION</b>iNOS plays dual roles in 629 metabolism, enhancing or decreasing the cytoxicity of 629 depending on the intracellular oxygen pressure P(O2), which caused higher cytotoxicity to hypoxia cells of 629 with the increasing of iNOS activity.</p>
Subject(s)
Humans , Antibiotics, Antineoplastic , Pharmacology , Aziridines , Pharmacology , Cell Cycle , Cell Line, Tumor , Cell Survival , DNA Damage , Fibrosarcoma , Metabolism , Pathology , Flow Cytometry , Indoles , Pharmacology , Mitomycin , Chemistry , Pharmacology , Nitric Oxide , Metabolism , Nitric Oxide Synthase Type II , Genetics , Metabolism , TransfectionABSTRACT
The feasibility of ablating differentiated adipocytes and the mechanism of cell ablation with a suitable prodrug activating system is described. The system is based on the use of E. coli nitroreductase (NTR) enzyme that activates certain nitro compounds, such as the antitumor drug CB1954, into cytotoxic DNA interstrand cross-linking agents. Differentiated preadipocyte cells (3T3L1) transfected with an aP2 driven nitroreductase construct were efficiently killed after incubation with medium containing the prodrug CB1954, while untransfected cells were not affected. It was demonstrated that the mechanism of cell ablation is apoptosis and that the system has a bystander effect mediated by a toxic metabolite of the prodrug. The described system should provide a good alternative approach for gene therapy studies and a new inducible approach to manipulating the number of cells in tissues of transgenic animals and the ability to study the recovery of the tissue from cell damage or loss.
Subject(s)
Animals , Mice , Adipocytes/drug effects , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Aziridines/pharmacology , Escherichia coli Proteins/genetics , Genes, Transgenic, Suicide/drug effects , Cell Culture Techniques , Cell Differentiation , Feasibility Studies , Time Factors , Transfection/methodsABSTRACT
Binary ethyleneimine [BEI] was used to inactivate the local Egyptian strain of sheep pox virus. The inactivation process was applied using final concentrations of BEI at 0.5, 1, 2 and 3% for different incubation periods at 37 dgree C. The virus was completely inactivated after 7 hours incubation with by 2% BEI final concentration; the inactivated virus was adsorbed on aluminium hydroxide gel when incubated for 6 hours in a concentration 1:1. The antibody levels were estimated by virus neutralization test and ELISA. Specific antibodies appeared from the 1[st] week post vaccination and remained until the 4[th] week post challenge. The prepared vaccine was evaluated for safety, sterility and potency. The vaccine proved to be safe, sterile and inducing protection for the vaccinated lambs when challenged by the virulent sheep pox virus up to 6 months post vaccination
Subject(s)
Animals , Vaccines , Aziridines/pharmacologyABSTRACT
A number of aziridine and bromomethyl acyclic phosphonates were prepared [7, 9] and studied for their cytotoxic effects on different tumor cell lines in vitro. All compounds have shown no cytotoxic activity in all the tumor cell lines utilized
Subject(s)
Aziridines , Antineoplastic Agents , Cytotoxicity Tests, Immunologic , Tumor Cells, Cultured/drug effectsABSTRACT
1 -AZIDO-4-phenyl-1,4-butanedione 2 proved to be a convenient precursor for the synthesis of a variety of heterocyclic systems through its treatment with some acidic and basic reagents. For example, 2-benzazepine-1,5-dione 3, 1,3-oxazolane-2,4-dione 4a, 1,3-thiazolane-2,4-dione 4b, 1,3-oxazol-5-one 5, quinazoline-2,4-dione 7, 4,6-diaryl-2-pyrimidineones 9a-d, 2,5-bis-substituted amino-1,3,4-oxadiazole II,5-aryl-2-N-substituted amino-1,3,4-oxadiazoles 13a,b, 1,2,4-triazol-3-ones 14a,b, 1,3-benzoxazine-2,4 [3H]-dione 15 and 1,3,4-oxadiazol-2[3H]-ones 16a,b
Subject(s)
Azides/chemistry , Aziridines/chemistry , Triazoles/chemistry , Acids, HeterocyclicABSTRACT
Se estudiaron cuatros operarios sobre un total de diez afectados, que trabajaban en una empresa de productos farmacéuticos para veterinaria que manipulaban etilenimina para la elaboración de vacuna antiaftosa. El objeto del presente trabajo fue determinar si la E. es el agente causal en diez operarios afectados por dermitis por contacto alérgica en una industria que la emplea y, en caso de confirmar esta participación, indicar las medidas de profilaxis respectiva
Subject(s)
Aziridines/adverse effects , Dermatitis, Contact/chemically induced , Aphthovirus/drug effects , Aziridines/immunology , Aziridines/metabolism , Dermatitis, Contact/etiology , Dermatitis, Contact/immunology , Dermatitis, Occupational/prevention & control , Skin Tests , Viral VaccinesABSTRACT
Bisazir, at a 0.5% solution induced sterility in males and at a 1.5% solution in female A. dirus. These sterilizing doses reduced P. falciparum infection in mosquitoes, however, they can still transmit malaria. It is concluded that by the concentration of 1.5 and 2.0% that induced complete sterility in males and females are not safe in sterile-male release programme for the control of A. dirus, unless all females were eliminated prior to release.