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Biomedical subjects

G Leclercq

Publications and source records attributed to G Leclercq.

At least 127 records · Page 7Linked to original sources
PubMed1989

Relation between estrogen receptor concentration and clinical and histological factors: their relative prognostic importance after radical mastectomy for primary breast cancer.

After modified radical mastectomy, 490 primary breast cancer patients were followed for a median of 75 months. Bloom grade was measured in 340 patients and ER status in 341. Follow-up of these patients has yielded the following results: (a) The value of traditional indices has been reaffirmed. (Cox's multivariate analysis identified, in order of decreasing importance, the number of invaded lymph nodes, the initial tumor size and the histological grade. Other variables were found to be of lesser importance and were correlated with the three main indices.) (b) The value of ER status disappeared after more than 3 years of follow-up. (c) ER positive patients fared better after recurrence. This was interpreted as being a consequence of their responsiveness to hormonal treatment.

Adult↗
PubMed1989

Diethylstilbestrol-linked cytotoxic agents: synthesis and binding affinity for estrogen receptors.

The syntheses of diethylstilbestrol derivatives with a C4 side chain at the double bond bearing various functional and potentially alkylating groups (9-25, 38-40, 43, 44) as well as the coupling product with daunorubicin (41) are described. Derivatives with free phenolic groups show easy isomerization to (Z)-stilbenes and styrenes, which could be minimized with silyl protecting groups. Estrogen receptor binding is decreased by polar groups such as carboxylic acids (10) as well as sterically demanding substituents.

Alkylation↗
PubMed1989

Hexestrol-linked cytotoxic agents: synthesis and binding affinity for estrogen receptors.

With the erythro-hexestrol derivative 2 as the starting material, a variety of cytotoxic linked hexestrol (HEX) compounds were prepared including the HEX-N-lost derivative 36, the HEX-(chloroethyl)nitrosourea 38, the HEX-cyclophosphamide 44, and the HEX-epoxide 68. Relative binding affinity to estradiol receptors were in the magnitude of 1%, similar to that of comparable diethylstilbestrol compounds. HEX derivatives with long polyether spacers (64, 65, 70, 71) showed no significant decrease in binding affinity in contrast to derivatives with other bulky side chains.

Antineoplastic Agents↗
PubMed1989

Derivatives of tamoxifen. Dependence of antiestrogenicity on the 4-substituent.

A range of tamoxifen derivatives substituted in the 4-position of the 1-phenyl ring are described. The key steps in the synthesis of 4-iodo-, 4-bromo-, and 4-(methylthio)tamoxifen were reactions of 1,2-diarylbutanones with the (4-halogenophenyl)lithium or [4-(methylthio)phenyl]magnesium bromide. Oxidized precursors of 4-(methylthio)tamoxifen were used to prepare the methylsulfinyl and methylsulfonyl derivatives. Further derivatives (formyl, hydroxymethyl, oxirane, mercapto) were prepared from 4-bromotamoxifen via the 4-lithio derivative. Several of the derivatives (Br, I, SMe, SOMe, SO2Me, oxirane, CHO, CH2OH) displayed a higher affinity for estrogen receptors (ER) of calf uterine cytosol than did tamoxifen, but there was no relationship between affinity to ER and the ability to inhibit the growth of the MCF-7 breast cancer cell line in vitro.

Animals↗
PubMed1989

[Intravenous thrombolysis with tissue plasminogen activator (rt-PA) at the prehospital phase of acute myocardial infarction. Apropos of 49 cases].

In acute myocardial infarction, the earlier intravenous thrombolysis is performed the more effective its action. Pre-hospital intravenous thrombolysis with 100 mg rt-PA was carried out in 49 patients within 3 hours of myocardial infarction. Male preponderance was conspicuous with 44 men (92%) and only 5 women (8%). Mean age was 50.2 +/- 8 years. The infarction was inferior in 48% of the cases. Out of the 49 thrombolyses performed by the mobile intensive care unit, 3 were discontinued on admission (2 diagnostic errors, 1 external heart massage). The time gained by pre-hospital thrombolysis was 52 +/- 25 minutes. There were few complications of thrombolysis: blood effusion at the site of puncture occurred in 4 cases (9%) and haematemesis in 1 case (2%). No cerebral or lethal haemorrhage was observed. Major complications of MI were seldom encountered at the pre-hospital phase: 1 patient died of extensive anterior necrosis with left ventricular dysfunction, and 2 had reversible ventricular fibrillation before treatment was initiated. There was no haemorrhagic complication. The earlier the patient was treated the lower the mortality and morbidity rates. Pre-hospital thrombolysis therefore seems to be feasible when performed by a mobile intensive care unit, and it represents an important gain of time.

Adult↗
PubMed1989

Analysis of the cytotoxic function of the thymocytes generated in a 14-day old mouse fetal thymus organ culture with high dose of IL-2.

The target cell specificity of LAK cells generated by addition of rIL-2 to thymic rudiments of 14 day old BALB/C embryo's was compared to the lytic potential of adult BALB/C splenic LAK cells. We used four tumor cell lines as targets, one NK-susceptible (YAC-1) and three NK-resistant tumors (C1300, P815 and EL4), which were all killed by splenic LAK cells. It is shown that fetal thymic LAK cells display a lower lytic activity, while EL4 tumor cells are not killed at all. By elimination of the CD8 positive cells from both the adult splenic and the fetal thymic LAK cells, we demonstrate that the fetal thymic LAK activity is mainly exerted by CD4-CD8- cells, whereas part of the cytotoxicity of splenic LAK cells is due to CD8+ cells.

Animals↗
PubMed1989

Influence of antibodies neutralizing cytokines on murine fetal thymic organ cultures.

The role of cytokines in early T cell development was evaluated in a thymic organ culture system. Fetal thymic lobes from 14 day old mouse embryo's were cultured in the presence of antibodies neutralizing either IL-4, IL6 or TNF. In addition antibodies neutralizing TNF were added to cultures supplemented with human recombinant IL-2. The influence of these different treatments were evaluated by analyzing the different subsets generated after 12 days of culture with a panel of monoclonal antibodies. The antibody treatment did not result in dramatic changes in the cell populations nor did the anti-TNF inhibit the significant changes that are induced by the IL-2 treatment. These results show that based on the cellularity and thymocyte subsets no influence can be shown by inhibiting these cytokines. Other criteria, e.g. repertoire specificity have to be evaluated to address the influence of these treatments on early T cell development.

Animals↗
PubMed1988

Non-isomerisable antiestrogens related to tamoxifen.

Three types of non-isomerisable antiestrogens analogous to tamoxifen and 4-hydroxytamoxifen are described. Advantages of non-isomerisability are simplified synthesis, simplified metabolism profile, and that structure-activity relationships become more meaningful. The compounds described differ from tamoxifen by having an extra ring methyl group, a fused seven-membered ring system, or the central ethylene linkage saturated. These compounds retained both binding affinity to estrogen receptors and growth inhibition of MCF-7 human breast cancer cells in vitro.

Animals↗
PubMed1988

Estrogen and antiestrogen interaction with estrogen receptor of MCF-7 cells--relationship between processing and estrogenicity.

Overnight preincubation of MCF-7 cells with 2 x 10(-10) M estradiol (E2) produces a dramatic reduction of their specific [3H]E2 binding capacity. Scatchard plot analysis revealed that this loss of estrogen receptor (ER) concentration, usually termed "processing", occurs without any significant modification of binding properties of the unprocessed receptors. Direct measurement of ER (ER-EIA from Abbott) gave residual receptor concentrations close to those established by binding assay indicating that processing involves the loss of at least one epitope other than the steroid binding site. Incubation with increasing amounts of E2 (0.1 to 5 x 10(-10) M) resulted in an increasing reduction of binding capacity indicating that the extent of processing is associated with the hormone concentration. Steroidal estrogens other than E2 as well as antiestrogens of the triphenylethylene category behaved similarly in this regard although the latter compounds usually acted only when at higher concentrations. The processing capacity of a large series of ligands was compared with the corresponding binding affinity for ER as assessed by classical competitive inhibition of [3H]E2 binding in both cytosol and whole cells. For steroidal estrogens, a large spectrum of concordant values was found which correlated with the known uterotrophic activity of the compounds. On the contrary, weak estrogen and antiestrogens of the triphenylethylene category displayed low processing capacities which were in the order of magnitude of the binding affinities established in whole cells; these values were considerably lower than the corresponding values measured in the cytosol. These observations are consistent with the concept that the capacity of a ligand to process ER is related to its agonistic activity. They also support our hypothesis (J. steroid Biochem. 25 (1986) 677-682) that assessment of the ability of a ligand to inhibit the binding of [3H]E2 in whole cells provides an estimate of its agonistic activity, an estimate which can not be established in the corresponding cytosol assay.

Binding, Competitive↗
PubMed1988

Enhanced oxygen metabolism of peritoneal macrophages in the presence of murine neuroblastoma cells is partly caused by enkephalins.

A bioluminescent technique was used to show that murine neuroblastoma (NB) cells or cell-free extracts (H variant) were able to enhance the release of reactive oxygen intermediates (ROI) from peritoneal macrophages in vitro. L-variant NB cells were ineffective. Physiological concentrations of met-enkephalin produced the same effect in vitro but not leu-enkephalin. When both H- and L-variant cells, or their extracts, were incubated together with macrophages, ROI production was not increased. Similar findings were detectable when met- and leu-enkephalin were cultured together with macrophages. In vivo, preliminary studies gave the same results. The concentration rate of met- to leu-enkephalin was higher in H-variant than in L-variant NB cells. We conclude from our results that met-enkephalin can enhance the release of ROI from peritoneal macrophages. The difference in the effects produced by the H and L variants is due to differences in the concentrations of enkephalins released.

Animals↗
PubMed1988

Nonisomerizable analogues of (Z)- and (E)-4-hydroxytamoxifen. Synthesis and endocrinological properties of substituted diphenylbenzocycloheptenes.

Substituted 8,9-diphenyl-6,7-dihydro-5H-benzocycloheptenes 6-8, which are ring-fused analogues of (Z)-trans-4-hydroxytamoxifen, (E)-cis-tamoxifen, and (E)-cis-4-hydroxytamoxifen, were synthesized from 7-methoxy-1-benzosuberone. The hydroxy compounds 6 and 8 were individually prepared via a common synthetic intermediate from which either the perfluoro-p-tolyl or the methyl ether functions could be cleaved specifically. Compounds were assayed for binding affinity to estrogen receptors in cytosol and in MCF-7 whole cells and for growth inhibition of MCF-7 cells in vitro and rat uteri in vivo. The endocrinological properties of the cyclic analogues 5-7 paralleled those of the corresponding derivatives of tamoxifen although in the MCF-7 assay 6 was slightly less effective than 4-hydroxytamoxifen at 10(-6) and 10(-7) M. The compound 8 analogues to cis-4-hydroxytamoxifen antagonized the growth stimulation by estradiol of MCF-7 cell or rat uterus growth, and it is therefore an antiestrogen, but its potency was somewhat less, both as an antiestrogen and an estrogen, than reported for cis-4-hydroxytamoxifen attributable to modification of the biochemical properties of the latter by isomerization to the more potent trans isomer. Curiously, in the absence of estradiol, compound 8 stimulated MCF-7 cell growth at low concentration (10(-8) M) but inhibited growth at higher concentration. In contrast, compound 7, which lacked the hydroxy function, was a full estrogen in the rat uterine growth assay. These compounds should be ideal for further structure-activity studies of triarylethylene-based antiestrogens without complications caused by isomerization.

Animals↗
PubMed1987

Cellular immunity changes caused by LDH virus: analogy with observations of neuroblastoma-bearing mice.

Evidence is presented that LDH virus infection of mice results in drastic changes in several immune activities. Serum IFN titer and splenic NK activity are increased during the acute phase of infection. NK stimulation is mediated by IFN-alpha,beta since injection of an antibody against murine IFN-alpha,beta is able to abolish the effect. IL-2 production is inhibited throughout the study period following injection of LDH virus (14 days), although a partial recovery is observed during the second week. Similarly, IL-2 receptor expression and MLC responsiveness are suppressed. This suppression lasts for 2 and 7 days respectively after injection. Addition of recombinant IL-2, but not of indomethacin, to the MLC cultures restores the proliferation rate. Not only proliferation but also cytotoxic cell generation in MLC is diminished during the first week after LDH virus injection. Again, this response is normalized at day 14. Additional observations indicate that LDH virus is present in murine neuroblastoma. This explains some of the previously described effects of this tumor on the cellular immune system of the host.

Animals↗
PubMed1987

Estrogen conjugates and serum factors mediating the estrogenic trophic effect on MCF-7 cell growth.

Estrogens stimulate growth of MCF-7 breast cancer cells in monolayer culture. Possible interference of serum factors leading to an estrogen-insensitive cell growth was analyzed in various experiments carried out on serum batches producing no estradiol stimulation. Out of five estrogen conjugates, only 3-glucurono-estradiol partly suppressed the inhibition of hydroxytamoxifen; the conjugate also reduced the estrogen receptor content of the cells, probably by a down regulation process ("processing"). Moreover, prolonged subcultures in dextran-coated charcoal-treated serum attempting to remove possible intracellular estrogens produced no growth stimulation. Interference by hormone carriers of the serum was ruled out by the fact that two strong synthetic estrogens, moxestrol and diethylstilbestrol with weak binding affinity for these carriers, were unstimulatory. Reduction of the carrier concentration also failed to confer any estrogen sensitivity. This lack of effect of most estrogen conjugates and serum carriers seems to contradict the hypothesis of their interference leading to an estrogen-insensitive growth. Presence in the serum of potential inhibitors towards estrogen action was also examined. Dilution of sera inducing an estrogenic stimulated growth failed to show any growth increase, either in the absence or presence of estradiol, thus excluding the possibility of a major influence of an antagonism on growth control. Moreover, clonogenic assays in soft agar eliminated the hypothesis that a difference between "active" (stimulatory with estradiol) and "inactive" serum batches may result from distinct adherence properties rather than from real growth stimulation. All of these data are consistent with the concept that serum factors which are not of estrogenic nature mediate the trophic effect of estradiol; their absence in some serum batches may lead to an estrogen-insensitive cell growth.

Animals↗
PubMed1987

Metabolism of tamoxifen by isolated rat hepatocytes. Identification of 1-[4-(2-hydroxyethoxy)phenyl]-1-(4-hydroxyphenyl)-2-phenyl-1-butene and the dependence of N-oxidation on oxygen availability.

Metabolism of tamoxifen by rat hepatocytes and hydrolysis of the resulting polar metabolites corresponding to conjugates with beta-glucuronidase gave a major component which was identified as 1-[4-(2-hydroxyethoxy)phenyl]-1-(4-hydroxyphenyl)-2-phenyl-1-butene by comparison of mass spectral properties with those of synthetic material. This compound, which was not observed as a phase I metabolite, is believed to have been found previously in rat bile and in human faeces (metabolite F) but its structure had been incorrectly assigned. Its binding affinity for the estrogen receptor was greater than that of tamoxifen but less than that of 4-hydroxytamoxifen, and it possessed a corresponding degree of antitumour activity against the MCF-7 breast cancer cell line. By carrying out the hepatocyte incubation separately under oxygen and air, it has been shown that the N-oxidation of tamoxifen is favoured by a high concentration of oxygen during in vitro metabolism but that the rate of 4-hydroxylation is not dependent on oxygen availability.

Animals↗
PubMed1987

Immune response to murine neuroblastoma: effects of in vitro culture of the tumor.

The humoral and cellular immune response of neuroblastoma (NB)-bearing mice has been investigated and shown to be dependent on the treatment of the NB tumor cells before implantation. Established lines and clones derived from the original tumor, as well as C1300 cells passaged in vitro, provoke an immune reaction which differs markedly from the one induced by the original C1300 tumor. Indeed, only the latter induces the formation of high amounts of circulating immune complexes (CIC), is able to trigger peritoneal macrophages in the host and to induce suppression, as shown in mixed lymphocyte cultures. After subculture of the tumor cells in vitro, none of these effects were observed. The pattern of immune response produced by tumor cells grown in vitro can be converted into the original type of response by repeated passaging of the tumor cells in vivo.

Animals↗