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At least 721 records · Page 40Linked to original sources
PubMed1977

Effects of acetylcholine mustard aziridinium ion and its choline analogue on choline transport into synaptosomes.

A compound thought to be choline mustard aziridimium ion was found previously in our laboratory to inhibit choline transport into human erythrocytes. Experiments with synaptosomes prepared from brain of rat now show that the aziridinium ion of choline mustard hydrochloride inhibited high- and low-affinity choline transport, with the inhibitory effect being about 10 times less than that of hemicholinium-3. Acetylcholine mustard aziridinium ion also inhibited the transport of choline, but it was less potent than its choline analogue. Studies with choline mustard aziridinium ion may yield important information about the transport of substances into the presynaptic nerve terminal.

Acetylcholine↗
PubMed1989

Hypoxia enhances the lethality of mitomycin C and carboquone against human malignant tumor cells in vitro.

Solid tumors contain hypoxic cells which are relatively resistant to antineoplastic activity of radiation or to chemotherapeutic agents. We determined the increase in antineoplastic activities of mitomycin C (MMC) and carboquone (CQ) against human tumor cells under conditions of in vitro hypoxia, with the following results. (a) The HeLa cells had been exposed to various concentrations of MMC or CQ for 2 h under normally aerated (about 20%) or hypoxic conditions (5.0 and 0%) and were maintained under normally aerated conditions for 3 days. The succinate dehydrogenase activity was assayed, using the succinate dehydrogenase inhibition (SDI) test. Treatment with MMC or CQ reduced the SD activity, compared to findings in the control cells, under hypoxic conditions. (b) The cells were exposed to the drug, MMC or CQ, under normally aerated or anoxic conditions, for 15-45 min and the colonies counted on day 14. Treatment with 0.45 microM of MMC for 45 min inhibited the clonogenicity of HeLa cells by 25.4% of findings in the control cells under anoxia. Treatment with 0.03 microM of CQ for 30 min inhibited the clonogenicity by 41.5%. (c) The sensitivity of 14 human tumor tissues (6 gastric and 8 colorectal cancers) to MMC or CQ under hypoxic conditions was determined, using the SDI test. MMC and CQ showed hypoxic enhancement. Therefore, MMC and CQ have definite positive effects on hypoxic cells, and hence a higher therapeutic ratio for treating clinical solid tumors.

Azirines↗
PubMed1981

Ability of a new antitumor agent, AZQ, to penetrate into cerebrospinal fluid.

The ability of a new antitumor agent, AZQ (2,5-diaziridinyl-3,6-bis-carboethoxyamino-1,4-benzoquinone), NSC No. 182986, to enter the cerebrospinal fluid (CSF) was studied in nonhuman primates. Following parenteral administration of 14C-AZQ, CSF radioactivity rose quickly and reached a maximum value 60 min after administration. Total radioactivity in the CSF was about 25-35% of the corresponding plasma level at time points subsequent to maximum CSF concentration. Chloroform extraction and thin-layer chromatography revealed that much of the total radioactivity was not parent AZQ and that parent AZQ declined rapidly in both plasma and CSF with a half-life less than 1 h. AZQ clearly entered the CSF and yielded CSF concentrations comparable to plasma values.

Animals↗
PubMed1983

Cytostatic activity of inorganic heterocycles in an in vitro screening system.

Six representatives of inorganic cyclic systems (NPAz2)2 NSOX(Az = aziridino, X = F, Az, Ph) and (NPAz2)2 NPAzR [R = Az, Morph (morpholino), Pyr (pyrrolidino)] show cytostatic activity in an in vitro screening system. The technique of the in vitro screening system used is described. L5178Y and Ehrlich ascites cells are grown as suspension cultures in concave-bottomed wells in microtiter test plates using serial dilutions of the drugs in the medium. The diameter of the cell sedimentation spots, which can be compared visually is taken to determine the lowest active dose. The results of this test correspond with the cytostatic activities observed in former in vivo experiments.

Animals↗
PubMed1987

Carboquone alters the protein synthesis of Chinese hamster V79 cell.

The effect of carboquone (CQ) on protein synthesis in Chinese hamster V79 cells was determined. While the syntheses of higher molecular weight proteins decreased, the relative level of a 43-kilodalton (kd) protein increased following exposure to CQ at the concentration of 0.5 microgram/ml, in a time-related fashion, determined using one-dimensional gel electrophoresis. Using two-dimensional gel electrophoresis, the 43-kd protein may be actin protein, and the syntheses of another two proteins of 8.5/45 and 4.8/270 (designated isoelectric point/molecular weight, kd) were increased in the CQ-treated V79 cells. These changes of the proteins induced by CQ in V79 cells were noted in HeLa cells. Three CQ-induced proteins are candidates for the elucidation of the antineoplastic effect of CQ.

Animals↗
PubMed1990

Detection of DNA strand breaks in HeLa cells in vitro and in mouse sarcoma 180 cells in vivo induced by an alkylating agent, carboquone, using in situ nick translation.

We determined the correlation between DNA strand breaks and the toxicity of carboquone (CQ) in HeLa cells in vitro and in mouse sarcoma 180 (S-180) cells in vivo, using in situ nick translation. The break sites in the DNA were translated artificially in the presence of Escherichia coli DNA polymerase I and [3-H]-labelled dTTP, and sites in the DNA were visualized by autoradiographic observation of grains in the nuclei. These breaks appeared as early as 5 min in the CQ-treated HeLa cells and increased in a dose- and time-dependent manner compared to findings in the control cells, i.e., 10.2-fold at 3 x 10(-6) M in 60 min. Strand breaks in the S-180 cells appeared in a dose- and time-dependent manner, i.e., 6.1-fold after the mice had been exposed to CQ (3.6 mg/kg) for 2 h. This level correlated with the increase in host life span. Our findings show that the survival response of cells decreases, while the level of DNA strand breaks increases following exposure to CQ. The nick translation method is a rapid in situ assay for determining drug-induced DNA damage of tumor cells, under in vitro and in vivo conditions and in a semiquantitative manner.

Animals↗
PubMed1987

Ketononestrol aziridine, an agonistic estrogen receptor affinity label: study of its bioactivity and estrogen receptor covalent labeling.

Ketononestrol aziridine [(6R,TS)1-(N-aziridinyl)6,7-bis-(4-hydroxyphenyl)5-nonamone (KNA)], an aziridine derivative of hexestrol, is an estrogenic affinity label for the estrogen receptor (ER). It has an apparent relative binding affinity 8% that of estradiol and shows time-dependent irreversible binding to the ER in uterine cytosol preparations and intact human breast cancer cells (MCF-7). The agonistic activity of KNA is evident in MCF-7 cells in culture, where it increases the cell growth rate and elevates the level of progesterone receptor. KNA was prepared in high specific activity tritium-labeled form by iodination of a methanesulfonate precursor, followed by catalytic tritium-iodine exchange and aziridinylation; the material prepared has high radiochemical purity and a specific activity of 67 Ci/mmol. The covalent attachment of [3H]KNA to the ER can be followed directly by a solvent precipitation assay. In cytosol preparations of uterine ER, labeling with [3H]KNA proceeds in a time-, concentration-, and temperature-dependent manner; labeling is efficient and selective and, by competition studies, was shown to be estrogen specific. ER in intact MCF-7 cells can also be covalently labeled by treatment with [3H]KNA. Receptor covalently labeled with [3H]KNA sediments as a 4S species on high salt sucrose gradients, and its sedimentation position is shifted by treatment with monoclonal antireceptor antibodies. On sodium dodecyl sulfate-polyacrylamide gels, the principal labeled species migrates with a mol wt of 66,000. KNA should prove to be a useful probe for studies on receptor structure, function, and chromatin interactions, particularly when the behavior of a receptor-agonist complex is being investigated.

Affinity Labels↗
PubMed1995

Molecular characterization by mass spectrometry of the human estrogen receptor ligand-binding domain expressed in Escherichia coli.

The ligand binding domain of the human estrogen receptor (hER-LBD), encompassing the sequence MDPS282AG...V595, has been expressed at high levels in Escherichia coli from a pET-23d vector, and a purified preparation has been characterized both by mass spectrometry and biochemical methods. Inclusion bodies from the bacterial expression were solubilized by sonication and the hER-LBD was purified to near homogeneity by affinity chromatography over an estradiol-Sepharose column in urea-containing buffer. This material ran as a single peak on reversed-phase HPLC, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis showed a band with apparent molecular mass of 31-32 kilodaltons (kDa), somewhat smaller than that expected from the construct (35.6 kDa). Edman degradation revealed a single sequence of MDPSAGDMRA, consistent with an intact N terminus. Further characterization of this material using low resolution matrix-assisted laser desorption ionization mass spectrometry indicated an apparent single protein species of average mass 33,143 daltons (Da). Detailed molecular analysis by electrospray ionization mass spectrometry, however, revealed that this purified hER-LBD preparation was actually composed of a number of both modified and unmodified LBD protein fragments between 32,900-33,400 Da. The bulk of this 33-kDa protein mixture consisted of three LBD protein fragments with C termini at Ala571 (70%), Ala569 (23%), and Ser575 (4%), with only a trace amount (3%) of the full length expressed LBD (MDPS282...V595; 35, 602 Da). These four protein species also appear to be partially chemically modified by carbamylation. The functional integrity of this hER-LBD preparation was investigated by a ligand-exchange assay, which showed that the hER-LBD retained full estradiol-binding capacity; specific, covalent labeling was also observed using either the electrophilic affinity-labeling ligand tamoxifen aziridine (TAZ) or the photoaffinity-labeling ligand hexestrol diazirine. Thus, this expressed hER-LBD preparation, while appearing nominally pure by conventional biochemical techniques and having the expected ligand-binding capacity, was shown by sensitive high resolution electrospray ionization mass spectrometry techniques to be largely truncated 20-26 amino acids from the expected C terminus and to have a substantial level of covalent modification arising from the urea.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1984

Treatment of patients with recurrent primary brain tumors with AZQ.

We have evaluated the efficacy of intravenous 2,5-diaziridinyl-3,6-biscarboethoxyamino-1,4-benzoquinone (diaziquone or AZQ, NSC-182986) in the treatment of recurrent primary anaplastic brain tumors. Three of 16 evaluable patients (18.8%) showed clinical and radiographic improvement that permitted discontinuation of corticosteroids, 4 patients (25%) showed either clinical or radiographic improvement and were considered partial responders, and 9 patients (56.2%) showed no effects after two courses of AZQ. The treatment was well tolerated, and hematologic toxicity was mild. Pharmacokinetic studies indicated rapid decay of the parent compound from plasma using two different infusion schedules. These results compare favorably with those obtained using the nitrosoureas or procarbazine as single agents.

Adolescent↗
PubMed1983

Intracerebral growth of a human glioma tumor line in athymic mice and treatment with procarbazine, 1,3-bis(2-chloroethyl)-1-nitrosourea, aziridinylbenzoquinone, and cis-platinum.

Tumors derived from the established human glioma cell line D-54 MG were transplanted intracerebrally into athymic "nude" mice. All control mice developed tumors in the brain after the transplantation of 10(5) cells and died within 30 days. Tumor was purely intracerebral in the presymptomatic stages, including the time of drug treatment. The injection of serial cell dilutions reduced the tumor incidence and prolonged survival. Procarbazine (PCB), 1,3-bis(2-chloroethyl)-1-nitrosourea, diaziquone (aziridinylbenzoquinone), and cis-platinum each produced statistically significant increases in survival when administered on Day 10 after transplantation, and PCB alone cured most of the animals. These results extend the characterization of the human glioma line D-54 MG and confirm the value of the athymic mouse for the testing of chemotherapeutic agents of interest in brain tumor therapy.

Animals↗
PubMed1997

Photoaffinity labeling of the ligand-interacting helix of the retinoic acid receptor alpha.

Two photoaffinity-labeling probes for retinoic acid receptor (RAR) alpha, 4-[(3-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl)carboxamido]ben zoic acid (3DIAM) and its para-isomer (4DIAM), were designed and synthesized. Both compounds possess high affinity for recombinant RAR alpha (MBP-RAR alpha/E) and bind covalently to its cognate ligand-binding site. The labeled site of MBP-RAR alpha/E with 3DIAM was determined, by the endoproteinase combination method, to be located in helix 11 of the ligand-binding domain of RAR alpha, which is the position at which the ligand is considered to bind, on the basis of the reported crystal structure of the retinoic acid/RAR gamma complex.

Azirines↗
PubMed1982

Studies on liposome-encapsulated carboquone II. Effect of liposomal encapsulation of carboquone on distribution and clearance in animals.

The effects of encapsulation of carboquone (CQ) in the liposomes were investigated on the plasma clearance and tissue distribution of CQ in rabbit and rat. CQ-Liposome, the liposomes in which CQ was encapsulated, was prepared by the method described in a previous report. By intravenous administration at the same dose. CQ-liposome showed approximately three times higher plasma concentration than free CQ in rabbit and rat. However, prolonged release from liposomes or stabilization of CQ in plasma was not observed by encapsulation. The distribution to lung and reticuloendothelial-rich organs such as liver and spleen was enhanced, but on the contrary the distribution to the peripheral tissues such as muscle and skin was decreased. In rats pretreated with drug free liposomes, high plasma CQ concentration was obtained after intravenous administration of CQ-liposome. From these results, it is considered that the large parts of CQ-liposome is distributed into reticuloendothelial system (RES) and RES is saturable with liposomes. And it is also presumed that the high plasma concentration obtained after intravenous administration of CQ-liposome, would be caused by altering the tissue distribution of CQ by encapsulation.

Animals↗
PubMed1982

Studies on liposome-encapsulated carboquone. III. Enhancement of lymphatic transport of carboquone by encapsulation.

To examine the possibility of utilizing liposomes as drug carriers of carboquone (CQ), an antitumor agent, effects of encapsulation on transport into lymphatics have been studied. Enhancement of lymphatic transport of CQ was obtained by the administration of liposome encapsulated CQ (CQ-liposome) into abdominal cavity in thoracic duct cannulated rats. And also, the enhancement of CQ transport into regional lymph nodes belong to gastrointestinal tract was also demonstrated in normal rats. When CQ-liposome was administered intravenously or intramuscularly, however, excellent transport into lymphatics was not recognized. Various pharmaceutical formation such as emulsions and oily solution failed to produce as high a lymph level as CQ-liposome. These results show that liposome may represent an effective system to deliver CQ into lymphatics by intraperitoneal administration.

Animals↗
PubMed1982

Studies on liposome-encapsulated carboquone. IV. Enhancement of antitumor activity of carboquone against Ehrlich ascites carcinoma by encapsulation.

The antitumor effects of liposome-encapsulated carboquone (CQ-liposome) were studied following intraperitoneal administration into mice bearing Ehrlich ascites carcinoma (EAC). CQ-liposome showed nearly 3 times superior efficiencies to parent CQ (free CQ) in the growth inhibitory effect on EAC cells inoculated in mice, and also showed almost the same toxicity as free CQ in normal mice. CQ-liposome prolonged the life span of EAC bearing mice about 2 times that of free CQ. In the results of electrophoresis, it was found that CQ-liposome and EAC cells had positive and negative surface charges, respectively. These observations suggest that CQ-liposome is a favorite delivery system to enhance the efficiency of CQ to EAC in mice. One of the reasons for its excellent effect may be explained by an easy contact of CQ-liposome with EAC cells because of its opposite surface charges.

Animals↗
PubMed1982

Effect of 1,3,3,5,5-pentaziridino-1-thia-2,4,6-triaza-3,5-diphosphorine-1-oxide, a new antitumor agent with inorganic ring, on various experimental tumors.

1,3,3,5,5-Pentaziridino-1-thia-2,4,6-triaza-3,5-diphosphorine-1-oxide (SOAz), a new antitumor agent, was evaluated for antitumor activity against various mouse- and rat-tumor systems. The optimal treatment regimens of SOAz (i.p.) gave 262% and 134% increase in life span (ILS) in mice with P388 leukemia and L1210 leukemia implanted intraperitoneally, respectively, and 239% ILS in rats with Yoshida sarcoma of which 86% survived for 60 d after intraperitoneal tumor implantation. The compound showed a definite activity against Lewis lung carcinoma implanted intravenously. The compound also exhibited 80-100% inhibition of tumor local growth in all of four experimental tumor systems used in the present study. In contrast to cyclophosphamide, SOAz was active against B16 melanoma and Meth A, and demonstrated high activity against a subline of L1210 leukemia resistant to cyclophosphamide.

Animals↗
PubMed1986

Interactions of anticancer quinone drugs, aclacinomycin A, adriamycin, carbazilquinone, and mitomycin C, with NADPH-cytochrome P-450 reductase, xanthine oxidase and oxygen.

The properties of the interactions of anticancer quinone drugs, aclacinomycin A, adriamycin, carbazilquinone, and mitomycin C with nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P-450 reductase and xanthine oxidase under anaerobic and aerobic conditions were studied. Km values of NADPH-cytochrome P-450 reductase for these drugs were in the range of 40-227 microM, and that of deflavo xanthine oxidase in the range of 39-over 200 microM. Under anaerobic conditions, when xanthine was used as an electron donor, deflavo xanthine oxidase catalyzed the reductive glycosidic cleavage reaction of anthracyclines and nicotinamide adenine dinucleotide was ineffective as an electron donor. In the electron spin resonance study, the formation of the semiquinone or free radical state of the quinone drugs in both enzyme systems were evidenced. A weak and symmetric signal was obtained from aclacinomycin A, and a symmetric signal from adriamycin was changed into an asymmetric and strong. The hyperfine structure was obtained from carbazilquinone in the oxidase system. In the studies of ultraviolet-visible spectra of the quinone drugs in the reductase system, the spectra of aclacinomycin A and adriamycin were changed to their 7-deoxylaglycones, and the formation of small amounts of the fully reduced form were observed after long incubations. The spectrum of carbazilquinone was changed to the hydroquinone form and mitomycin C was converted into mitosene analogues. Under aerobic conditions, superoxide radicals and hydrogen peroxide were effectively produced in the presence of anticancer quinone drugs in both enzyme systems. The superoxide-dependent hydroxy radical production, which was measured by ethylene production from methional, was observed in the presence of aclacinomycin A and adriamycin in the deflavo xanthine oxidase system. From these results, the possible reactions in the interactions of anticancer quinone drugs with these enzymes and oxygen are discussed.

Aclarubicin↗