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1.
Normal and transformed human fibroblasts were treated for either 1 sec or 1 h with the antitumor drug cis-dichlorodiamine platinum (cisplatin). The dose response of drug binding and cell survival was determined for cells treated with the drug in the presence or absence of 3.0 mM CaCl2. The levels of drug initially bound to both cell types was similar and was not affected by the presence of Ca2+. The dividing non-transformed cells were most sensitive to killing by short treatment with cisplatin compared to the transformed cells or the confluent non-transformed cultures. After 1 h of cisplatin treatment, the levels of drug bound to the cells were significantly less than that recovered after the shorter treatment. This time-dependent loss of cisplatin was inhibited both by CaCl2 and by the calcium channel blocking agent, verapamil. The higher levels of cisplatin bound after 1 h in the presence of these agents, however, did not in all cases result in decreased survival; the effects were dependent on cell type and on whether the cells were dividing or confluent. Analysis of cisplatin binding to cell cultures indicated that initially the cisplatin was weakly attached to the pericellular and substratum attached material but that with time, the drug bound to this material decreased. This time-dependent removal from the extracellular matrix was much less in the transformed cell cultures and was inhibited by calcium. We propose that the major site of interaction of cisplatin with these cells is in the extracellular matrix and with time the cultures alter their extracellular matrix to decrease this binding. This removal process appears to involve calcium or calcium transport since CaCl2 and verapamil both block these changes. 相似文献
2.
L-641,953 (R-8-fluoro-dibenzo[b, f]thiepin-3-carboxylic acid-5-oxide): a novel thromboxane-prostaglandin endoperoxide antagonist 总被引:1,自引:0,他引:1
R A Hall J R Rokach P Bélanger L Bianchi D Ethier A W Ford-Hutchinson Y Girard P Hamel R Hamel A Lord 《Canadian journal of physiology and pharmacology》1987,65(4):509-514
The effects of L-641,953 (R-8-fluoro-dibenzo[b, f]thiepin-3-carboxylic acid-5-oxide) have been studied on pulmonary and other smooth muscle preparations in vitro and in vivo. When studied in vitro on guinea-pig tracheal chains, L-641,933 produced significant shifts in the dose-response curves to the prostaglandin endoperoxide analogues, U-44069 (pA2 7.06) and U-46619 (pA2 7.14), and prostaglandin (PG) F2 alpha (pA2 6.33) had minimal activity against contractions induced by histamine (pA2 4.38), 5-hydroxytryptamine (pA2 4.63), and acetylcholine (pA2 4.56) and slightly enhanced relaxation induced by PGE2. When tested on the guinea-pig gall bladder strip in vitro, L-641,953 antagonized contractions induced by U-44069 (pA2 7.03) but was less active against those induced by PGF2 alpha (pA2 6.03), PGE1 (pA2 5.62), and histamine (pA2 4.84). When tested in vitro on the guinea-pig pulmonary artery, L-651-953 significantly antagonized contractions induced by U-44069 (pA2 7.04), U-46619 (pA2 7.14), and PGF2 alpha (pA2 7.16) but was less effective against contractions induced by histamine (pA2 4.19). Schild analysis indicated that L-641,953 was fully competitive against contractions of either the guinea-pig tracheal chain induced by U-46619 or the guinea-pig pulmonary artery induced by U-44069 and U-46619. When tested on human platelets in vitro L-641,953 inhibited aggregation induced by U-44069 (IC50 1.3 X 10(-6) M) but not ADP.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
3.
alpha 1-Proteinase inhibitor (alpha 1-PI), a member of the serine
proteinase inhibitor superfamily, has a primary role in controlling
neutrophil elastase activity within the mammalian circulation. Several
studies have indicated that the reactive center region of alpha 1-PI, the
amino acid sequence of which is critical to recognition of and binding to
target proteinases, is highly divergent within and among species. This
appears to be a consequence of accelerated rates of evolution that may have
been driven by positive Darwinian selection. In order to examine this and
other features of alpha 1-PI evolution in more detail, we have isolated and
sequenced cDNAs representing alpha 1- PI mRNAs of the mouse species Mus
saxicola and Mus minutoides and have compared these with a number of other
mammalian alpha 1-PI mRNAs. Relative to other mammalian mRNAs, the extent
of nonsynonymous substitution is generally high throughout the alpha 1-PI
mRNA molecule, indicating greater overall rates of amino acid substitution.
Within and among mouse species, the 5'-half of the mRNA, but not the
3'-half, has been homogenized by concerted evolution. Finally, the reactive
center is under diversifying or positive Darwinian selection in murid
rodents (rats, mice) and guinea pigs yet is under purifying selection in
primates and artiodactyls. The significance of these findings to alpha 1-PI
function and the possible selective forces driving evolution of serpins in
general are discussed.
相似文献
4.
Anti-idiotypic mimicry of a neutralizing epitope on the glycoprotein B complex of human cytomegalovirus. 总被引:1,自引:1,他引:0
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Experiments were carried out to investigate the ability of rabbit anti-idiotype antibodies (Ab2), directed against an anti-human cytomegalovirus monoclonal antibody (Ab1), to induce neutralizing antibodies specific for the immunodominant glycoprotein B viral complex. Mice immunized with Ab2 produced anti-Ab2 (Ab3) that was both antigen and idiotype specific with regard to Ab1. We conclude that the Ab2 antibodies mimicked a neutralizing epitope and acted as a network antigen for inducing a specific anti-human cytomegalovirus antibody response in this experimental system. 相似文献
5.
Vanadium (V) is an orally effective treatment for diabetes, but relatively little is known about the mechanisms controlling its normal metabolism nor the long term pharmacokinetics of oral administration. We have examined the accumulation of V in various organs from rats fed liquid diet for up to 18 days, containing no additional V, 1.6, 80, or 160 mole/kg/day as either sodium orthovanadate (SOV) or vanadyl sulfate (VS). V content was assayed using a sensitive neutron activation analysis method. The organs of the nonsupplemented animals contained widely varying concentrations (ng of V/g dry tissue weight) with brain < fat < blood < heart < muscle < lung < liver < testes < spleen < kidney. All organs accumulated V in a dose dependent manner. Not all organs showed steady state amount of V at 18 days, so additional rats were fed SOV or VS, switched to control diet, and assayed at 0, 4 and 8 days. From this data we calculated organ half lives of V. Insulin sensitive tissue tissues, such as liver and fat, had shorter half-lives than tissues that are relatively less insulin sensitive, such as spleen, brain and testes. SOV and VS fed rats showed similar patterns, but VS had somewhat shorter t1/2's. Additional studies of old and young rats fed control diet for 45 days show accumulation of V in spleen and testes. These results indicate that vanadium metabolism varies widely among different organs, and that insulin, either directly or indirectly has effects on the retention of vanadium. This may have impact on the therapeutic use of vanadium in Type I diabetics with no insulin, or Type II patients who may be relatively hyperinsulinemic. 相似文献
6.
Qian Shi Pascal Verdier-Pinard Arnold Brossi Ernest Hamel Kuo-Hsiung Lee 《Bioorganic & medicinal chemistry》1997,5(12):2277-2282
(+)-Thiocolchicine (2b) was prepared from (±)-colchicine (1) in a five-step reaction sequence that included chromatographic separation of appropriate camphanylated diastereomers. Acid hydrolysis of the (+)-diastereomer, followed by acetylation, yielded the desired product 2b. (+)-Thiocolchicine has 15-fold lower inhibitory activity against tubulin polymerization than (−)-thiocolchicine, and is 29-fold less potent for inhibiting growth of human Burkitt lymphoma cells. The enantiomer 2a, prepared from the (−)-camphanylated diastereomer, had potent activity in all assays comparable to that of (−)-thiocolchicine prepared by other methods. These results support the hypothesis that the proper configuration of colchicine-related compounds is an important requirement for their anti-tubulin action. 相似文献
7.
G Waksman E Hamel R Bouboutou R Besselièvre M C Fournié-Zaluski B P Roques 《Comptes rendus de l'Académie des sciences. Série III, Sciences de la vie》1984,299(14):613-615
The first visualization of enkephalinase (neutral metalloendopeptidase, E.C.3.4.24.11) in rat brain was obtained by autoradiography, using a new tritiated inhibitor: [3H]N-[( R,S )3-(N-hydroxy) carboxamido-2-benzyl propanoyl]glycine (3H-HCBP-Gly). The preliminary analysis of sections clearly showed a discrete localization of enkephalinase in enkephalin enriched regions, such as caudate nucleus, putamen, globus pallidus, and substantia nigra. Moreover 3H-HCBP-Gly binding also occurred in choroid plexus and spinal cord. 相似文献
8.
T Jones P Masson R Hamel G Brunet G Holme Y Girard M Larue J Rokach 《Prostaglandins》1982,24(2):279-291
The biological activity of synthetic leukotriene C4, D4 and E4 sulfone has been determined in respiratory smooth muscle in vitro and in vivo. The sulfones of LTC4, LTD4 and LTE4 were potent contractile agonists on indomethacin-treated guinea pig tracheal chains with respective pD2-values of 8.2, 8.0 and 7.9. Contractions were submaximal (75-85% of the cholinergic maximum), slow in onset, prolonged in duration, slowly reversed by washing (compared to acetylcholine or histamine) and were partially reversed by 2 muM FPL-55712. The sulfones of LTC4, LTD4 and LTE4 also contracted indomethacin-treated guinea pig parenchyma (respective pD2's of 7.9 8.2 and 7.8) and rat parenchyma (respective pD2's of 7.1, 7.2 and 7.2) but were inactive on rat trachea (0.01-2.0 muM). When administered intravenously to anaesthetized guinea pigs, the sulfones of LTD4, LTE4 and to a lesser degree LTC4 (respective ED50's - 0.5; 2.0 and 4.6 microgram/kg) elicited dose-dependent increases in inflation pressure which were antagonized by FPL-55712 and indomethacin. Leukotriene C4, D4 and E4 sulfones display a qualitatively similar profile of biological activity to that of their corresponding sulfides. 相似文献
9.
10.
R L Bai K D Paull C L Herald L Malspeis G R Pettit E Hamel 《The Journal of biological chemistry》1991,266(24):15882-15889
Data generated in the new National Cancer Institute drug evaluation program, which is based on inhibition of cell growth in 60 human tumor cell lines, were used to compare new compounds with agents of known mechanism of action in terms of their differential cytotoxicity. Two marine natural products, halichondrin B and homohalichondrin B, appeared repeatedly when the data base was probed with known antimitotic agents. We confirmed that both compounds were highly cytotoxic (IC50 values for L1210 murine leukemia cells of 0.3 and 1 nM, respectively), with accumulation of cells arrested in mitosis at toxic concentrations, that both inhibited the polymerization of purified tubulin, and that both inhibited microtubule assembly dependent on microtubule-associated proteins. Limited amounts of homohalichondrin B, the less active agent, were available, so only halichondrin B was studied in detail. Halichondrin B did not interfere with colchicine binding to tubulin, but it was a noncompetitive inhibitor of the binding of vinblastine to tubulin (apparent Ki, 5.0 microM). Halichondrin B was therefore compared with other agents which interfere with the binding of vinca alkaloids to tubulin (vinblastine, maytansine, dolastatin 10, phomopsin A, rhizoxin) in terms of its effects on tubulin polymerization, inhibition of GTP hydrolysis, inhibition of nucleotide exchange, and stabilization of tubulin, as well as the quantitative assessment of its effects on vinca alkaloid binding and inhibition of cell growth. Since halichondrin B was originally isolated from the same organism as the phosphatase inhibitor okadaic acid, and since it is about 50-fold more effective than okadaic acid as an inhibitor of L1210 cell growth, perturbations of cellular microtubules observed following treatment with okadaic acid should be interpreted cautiously. 相似文献