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Biomedical subjects

M Perez

Publications and source records attributed to M Perez.

At least 55 records · Page 3Linked to original sources
PubMed2000

EGF receptor and p21WAF1 expression are reciprocally altered as ME-180 cervical carcinoma cells progress from high to low cisplatin sensitivity.

Cell cycle regulators and signal transduction pathways can influence apoptotic sensitivity of tumor cells, and we previously described an association between EGFr overexpression, reduced DNA repair activity, and increased apoptotic sensitivity of ME-180 cervical carcinoma cells toward cis-diammedichloroplatinum (cDDP; K. Nishikawa, et al., Cancer Res., 52: 4758-4765, 1992). In the present study, the characteristics of ME-180 cells selected for high or low apoptotic sensitivity to cDDP (or camptothecin) were examined and compared to determine whether signal transduction components and cell cycle regulation were distinct in these isogenic drug response variant populations. As ME-180 cells progressed from high to low cDDP sensitivity [IC50 approximately 80 ng/ml in cDDP sensitive (PT-S) to approximately 2000 ng/ml in cDDP-resistant (Pt-R) cells], there was a significant decrease in EGFr expression that paralleled the relative reduction in cDDP apoptotic responsiveness (approximately 30-fold). cDDP-resistant cells had the slowest rate of growth and more effectively reduced DNA adduct levels following cDDP exposure than parental cells. Cellular levels of the cell cycle inhibitor p21WAF1 inversely correlated with cDDP responsiveness with high levels of p21WAF1 expressed in drug-resistant Pt-R cells in the absence of elevated p53. cDDP stimulated a 2-fold increase in p53 levels in both drug-sensitive and drug-resistant cells but caused a delayed reduction in p21WAF1 levels, suggesting p53-independent regulation of p21WAF1 in ME-180 cells. Activation of EGFr in Pt-R cells stimulated cell cycle progression (2-fold), reduced p21WAF1 levels (>2-fold), and increased sensitivity to cDDP (3-fold), suggesting that receptor signaling enhanced the efficacy of cDDP to induce cell death by relieving cell cycle restriction. These results demonstrate that the transition of ME-180 cells from a drug-sensitive to drug-resistant phenotype correlates with reciprocal changes in EGFr and p21WAF1 expression and provides additional evidence that the pathways controlled by these proteins may contribute to some forms of drug resistance.

Apoptosis↗
PubMed2000

[Pituitary development and pathology of transcription factors].

Over the last 10 years, important data on pituitary development have been reported using spontaneous or experimental models of gene inactivation. The development pathways of the anterior pituitary lobe include organogenesis resulting in Rathke pouch formation and cell differentiation. Pituitary development is controlled by sequential series of specific signaling molecules and specific transcription factors. In humans, inactivation of Pit-1, Prop-1, Rpx and Ptx2 genes is responsible for pituitary combined deficiency. In this paper, updated data on the embryology of the pituitary gland and the clinical phenotypes of inactivation of pituitary transcription factors are reported.

Animals↗
PubMed2000

In vivo K-edge imaging with synchrotron radiation.

We present in this paper two imaging techniques using contrast agents assessed with in vivo experiments. Both methods are based on the same physical principle, and were implemented at the European Synchrotron Radiation Facility medical beamline. The first one is intravenous coronary angiography using synchrotron radiation X-rays. This imaging technique has been planned for human studies in the near future. We describe the first experiments that were carried out with pigs at the ESRF. The second imaging mode is computed tomography using synchrotron radiation on rats bearing brain tumors. Owing to synchrotron radiation physical properties, these new imaging methods provide additional information compared to conventional techniques. After infusion of the contrast agent, it is possible to derive from the images the concentration of the contrast agent in the tumor area for the computed tomography and in any visible vessel for the angiography method.

Animals↗
PubMed2000

Recent progress in protein farnesyltransferase inhibition.

This review aims to provide a recent update on protein farnesyltransferase inhibition, covering the period 1999 to mid 2000. A brief overview of the project rationale and its most recent evolution is also presented. For each inhibitor series, the most advanced molecules are presented along with a short description of the patent environment, focusing on second generation patents that cover new applications for protein farnesyltransferase inhibitors (PFTIs).

Journal Article↗
PubMed1999

Magnitude of 5-HT1B and 5-HT1A receptor activation in guinea-pig and rat brain: evidence from sumatriptan dimer-mediated [35S]GTPgammaS binding responses.

The present study reports on G-protein activation by recombinant 5-HT receptors and by native 5-HT1A and 5-HT1B receptors in guinea-pig and rat brain using agonist-stimulated [35S]GTPgammaS binding responses mediated by a new 5-HT ligand, a dimer of sumatriptan. Dimerization of sumatriptan increased the binding affinity for h 5-HT1B (pKi: 9.22 vs. 7.79 for sumatriptan), h 5-HT1D (9.07 vs. 8.08) and also h 5-HT1A receptors (7.80 vs. 6.40), while the binding affinity for h 5-ht1E (6.67 vs. 6.19) and h 5-ht1F (7.37 vs. 7.78) receptors was not affected. Sumatriptan dimer (10 microM) stimulated [35S]GTPgammaS binding mainly in the superficial gray layer of the superior colliculi, hippocampus and substantia nigra of guinea-pig and rat coronal brain sections. This fits with the labelling by the 5-HT1B/1D receptor antagonist [3H] GR 125743. The observed [35S]GTPgammaS binding responses in the substantia nigra are likely to be mediated by stimulation of the 5-HT1B receptor subtype, since they were antagonized by the 5-HT1B inverse agonist SB 224289 (10 microM), and not by the 5-HT2A/1D antagonist ketanserin (10 microM). Quantitative assessment of the [35S]GTPgammaS binding responses in the substantia nigra of rat showed highly efficacious responses for both sumatriptan dimer and its monomer. In contrast, less efficacious agonist responses (51+/-10% and 35+/-13%, respectively) were measured in the guinea-pig substantia nigra. This may suggest that the G-protein coupling efficacy of 5-HT1B receptors is different between the substantia nigra of both species. In addition, the sumatriptan dimer also activated guinea-pig and rat hippocampal 5-HT1A receptors with high efficacy in contrast to sumatriptan. Therefore, dimerization of sumatriptan can be considered as a new approach to transform a partial 5-HT1A agonist into a more efficacious agonist. In conclusion, the sumatriptan dimer stimulates G-protein activation via 5-HT1B receptors besides 5-HT1A receptors in guinea-pig and rat brain. The magnitude of the 5-HT1B receptor responses is superior for sumatriptan and its dimer in rat compared to guinea-pig substantia nigra.

Animals↗
PubMed1999

Oxandrolone, used for treatment of wasting disease in HIV-1-infected patients, does not diminish the antiviral activity of deoxynucleoside analogues in lymphocyte and macrophage cell cultures.

Antiviral agents are the primary therapy for patients infected with HIV-1. However, supportive therapies are often necessary in addition to antiviral drugs because of the devastating wasting process associated with HIV-1 infection and AIDS. Oxandrolone, an anabolic steroid, is used in promoting weight gain and, most important lean body mass (LBM), in patients with HIV-1 disease. We investigated whether oxandrolone interferes with the antiviral activity of zidovudine (ZDV), dideoxyinosine (ddI), and dideoxycytidine (ddC) on HIV-1 replication in peripheral blood lymphocytes and macrophage-monocytes. The nucleoside analogues had nanomolar 50% inhibitory concentrations (IC50) in peripheral lymphocytes. Combinations of nucleoside analogues and oxandrolone did not result in increased IC50 values. Oxandrolone used alone exhibited micromolar IC50 values in peripheral blood lymphocytes. Lack of interference was consistent for nucleoside concentrations up to 5 microM and for oxandrolone concentrations up to 100 microM in several combinations of drugs, viral strains, and peripheral lymphocytes and macrophages. We conclude that oxandrolone can be used for the promotion of weight gain in patients with AIDS-related wasting without interference with the antiviral effects of ZDV, ddI, or ddC.

Anabolic Agents↗
PubMed1999

Differential expression and translocation of protein tyrosine phosphatase 1B-related proteins in ME-180 tumor cells expressing apoptotic sensitivity and resistance to tumor necrosis factor: potential interaction with epidermal growth factor receptor.

Tumor necrosis factor (TNF)-induced apoptosis can be inhibited by overexpression of specific tyrosine kinases or activation of tyrosine kinase cascades, suggesting potential antagonism between apoptotic and tyrosine kinase signaling processes. In this report, the effects of TNF on EGF receptor tyrosine phosphorylation in ME-180 cell variants selected for apoptotic sensitivity (Sen) or resistance (Res) to TNF, previously shown to differentially express EGFr, were examined. Prior to the onset of apoptosis, TNF caused a significant reduction in the level of EGFr tyrosine phosphorylation in Sen cells but mediated only limited suppression of EGFr tyrosine phosphorylation in apoptotically resistant Res cells. In vitro incubation of cellular membranes with TNF derived from Sen cells stimulated a resident protein tyrosine phosphatase (PTP) activity which was able to dephosphorylate EGFr or tyrosine phosphopeptides mimicking an EGFr autophosphorylation site. In membrane preparations, PTPIB complexed with tyrosine phosphorylated EGFr and this association was disrupted by TNF through an apparent stimulation of PTP activity and turnover of phosphotyrosine. Intrinsic enzymatic activity of PTP1B was 2-3-fold higher in Sen versus Res cell lysates and a family of PTP1B-related proteins with altered C-termini was found to be highly expressed in Sen cells but absent or expressed at reduced levels in Res cells. Cytoplasmic extracts of Sen cells contained PTP1B-like proteins and TNF incubation resulted in the time dependent accumulation of PTP1B-like proteins in Sen cells but did not effect these proteins in Res cells. Together, these results suggest that specific changes in expression and subcellular distribution of phosphotyrosine modulatory proteins may play a role in conveying intrinsic apoptotic sensitivity to TNF in some tumor cell types.

Apoptosis↗
PubMed1999

Transfer of EBV-specific CTL to prevent EBV lymphoma post bone marrow transplant.

EBV-associated lymphoproliferative disorders (EBV-LPD) are a significant problem after hemopoietic stem cell transplantation from unrelated donors or mismatched family members. Risk factors include T-cell depletion, MHC mismatch, and intensity of immunosuppression. New therapeutic strategies involve cellular immunotherapy approaches and both donor T-cells and EBV-specific cytotoxic T lymphocytes (CTLs) have proven to be effective therapies. EBV-specific CTL has also proved to have a major impact on the incidence of this complication when used prophylactically.

Antibody Specificity↗
PubMed1999

Selective upregulation of MHC class I expression in metastatic colonies derived from tumor clones of a murine fibrosarcoma.

Eighteen metastatic nodes derived from the wild-type (GR9) and from 4 different clones (G2, D8, B10, and B9) obtained from a fibrosarcoma were analyzed for H-2 class I and II expression, as well as for adhesion molecules (CD44, CDIIb, CD18, CD49, and CD54). When metastatic nodes were cultured, typed for H-2 antigens, and compared with the H-2 expression of the inducing tumor cell, H-2 Kd and Dd class I expression was greater in most nodes analyzed. In contrast, the Ld molecule remained negative, or showed a minor increase. Class II expression was negative in the wild-type and the tumor clones, and remained so in the metastatic colonies. Analysis of the adhesion molecules revealed no differences between the inducing tumor cells and the metastatic nodes. The only molecule expressed was CD44, which was present in all cells studied and was also inducible by interferon-gamma. The increase in H-2K and H-2D expression was associated with resistance to natural killer cytotoxicity, as observed in the G2 tumor clone and some autologous metastases, such as B9MP2, G2MK2, and G2MLI. In three independent clones of this tumor system (D8, BIOMP6, and B9MP6) we found that tumor cells treated with interferon-gamma had the same altered phenotype, i.e., a selective lack of response of the Ld molecule to induction. These findings add a cautionary note to the well-established idea that tumor cells may lose all class I antigens during tumor progression, and suggest that sometimes this may not be the case. The selective downregulation of Ld and upregulation of Kd and Dd class I expression may give some tumor cells means of escaping both cytotoxic lymphocyte and natural killer immune surveillance.

Animals↗
PubMed1999

JNK and p53 stress signaling cascades are altered in MCF-7 cells resistant to tumor necrosis factor-mediated apoptosis.

Tumor necrosis factor (TNF) signal transduction is a complex process involving activation of receptor-linked and stress-sensitive signaling cascades that stimulate apoptosis in some tumor cell lines. Initial studies suggested that these signaling events cooperatively induced TNF responses, but recent studies suggest that some of these signals antagonize the apoptotic response or play no discernible role in cell death. As TNF induces cellular stress and activates several stress-sensitive cascades that may play a role in apoptosis, TNF-induced stress signaling was examined in MCF-7 cells and compared with a variant MCF-7 cell line resistant to TNF-mediated apoptosis (MCF-7/3E9). TNF rapidly stimulated both NF-kappaB and JNK activation in MCF-7 and MCF-7/3E9 cells, but JNK activation was significantly reduced (threefold) in apoptotically resistant cells. TNF also stimulated p53, p21WAF1, and Bax accumulation with subsequent PARP cleavage and nucleosomal DNA laddering in MCF-7 cells but did not stimulate these processes in MCF-7/3E9 cells. Importantly, 3E9 cells retained wild-type p53 function, induced p21WAF1 in response to DNA damage, and expressed almost equal sensitivity to other stress stimuli (gamma-radiation, chemotherapeutic agents) as parental MCF-7 cells. These results suggest that selective defects in TNF-activated stress cascades are associated with reduced sensitivity to TNF but not other cell death stimuli. Loss of potent TNF-mediated activation of JNK and p53 cascades may permit tumor cells to evade receptor-mediated apoptosis but have only limited influence on cellular sensitivity to other agents that effectively engage these stress pathways.

Apoptosis↗
PubMed1999

Allergy of anaesthetizing agents in Spain.

We have investigated the incidence of requests for allergy testing in 5005 patients attending an anaesthetic assessment clinic. Diagnosis of allergy to anaesthetic drugs was established using cutaneous tests. Allergy tests were requested in 151 (3.0%) patients, proving positive in 43 (0.86%). No allergic reactions were observed during subsequent anaesthesia.

Adolescent↗
PubMed1999

Stroke in Hispanic veterans: a descriptive study.

BACKGROUND: Differences in risk factor prevalence and distribution of atherosclerotic cerebrovascular disease have been reported among different racial-ethnic groups. Identification of stroke syndromes and risk factors specific to the Puerto Rican male population should lead to more effective diagnosis, treatment, and prevention programs. METHODS: We prospectively and consecutively evaluated 118 Hispanic male veterans admitted to our Stroke Unit from June 1994 to September 1995. RESULTS: Ninety patients (76%) had an ischemic infarct, 26 (22%) had a transient ischemic attack, and 2 (2%) had an intracerebral and/or subarachnoid hemorrhage. Hypertension was the most common risk factor. Echocardiographic studies were done in 64% of the patients, and the most common findings were concentric left ventricular hypertrophy and diastolic dysfunction. Cerebral angiography was done in 40 cases, and findings were abnormal in 32 (80%). CONCLUSIONS: We believe this is the largest descriptive study of Hispanic male veterans with stroke syndromes. It provides baseline data to serve as a comparison group for future research.

Adult↗
PubMed1999

F 11356, a novel 5-hydroxytryptamine (5-HT) derivative with potent, selective, and unique high intrinsic activity at 5-HT1B/1D receptors in models relevant to migraine.

F 11356 (4-[4-[2-(2-aminoethyl)-1H-indol-5-yloxyl]acetyl]piperazinyl-1-yl] ben zonitrile) was designed to take advantage of the superior potency and efficacy characteristics of 5-hydroxytryptamine (5-HT) compared with tryptamine at 5-HT1B/1D receptors. F 11356 has subnanomolar affinity for cloned human and nonhuman 5-HT1B and 5-HT1D receptors, and its affinity for 5-HT1A and other 5-HT receptors, including the 5-ht1F subtype, is 50-fold lower and micromolar, respectively. In C6 cells expressing human 5-HT1B or human 5-HT1D receptors, F 11356 was the most potent compound in inhibiting forskolin-induced cyclic AMP formation (pD2 = 8.9 and 9.6), and in contrast to tryptamine and derivatives, it produced maximal enhancement of [35S]guanosine-5'-O-(3-thio)triphosphate-specific binding equivalent to 5-HT. F 11356 was equipotent to 5-HT (pD2 = 7.1 versus 7.2) and more potent than tryptamine derivatives in contracting rabbit isolated saphenous vein. In isolated guinea pig trigeminal ganglion neurons, F 11356 was more potent (pD2 = 7.3 versus 6.7) and induced greater increases in outward hyperpolarizing Ca2+-dependent K+ current than sumatriptan. In anesthetized pigs, F 11356 elicited highly cranioselective, more potent (from 0.16 microgram/kg i.v.) and greater carotid vasoconstriction than tryptamine derivatives. Decreases in carotid blood flow were observed in conscious dogs from 0.63 mg/kg oral F 11356 in the absence of changes in heart rate or behavior. Oral activity was confirmed when hypothermic responses were elicited in guinea pigs (ED50 = 1.6 mg/kg), suggesting that F 11356 also accesses the brain. F 11356 thus is a selective, high-potency agonist at 5-HT1B/1D receptors, which distinguishes itself from tryptamine and derivatives in exerting high intrinsic activity at these receptors in vascular and neuronal models relevant to migraine.

Animals↗
PubMed1998

Dimers of 5HT1 ligands preferentially bind to 5HT1B/1D receptor subtypes.

New dimers of known 5HT1 ligands (5HT, 1-NP or 8-OH-DPAT) have been prepared and evaluated at human cloned 5HT1B, 5HT1D and 5HT1A receptors. Binding experiments show that all these dimers have better affinities at 5HT1B/1D receptors than their corresponding monomeric ligands. Studies of inhibition of the forskolin-stimulated c-AMP formation mediated by the human 5HT1B receptor show that hetero-bivalent ligands [combining an agonist (5HT) with an antagonist (1-NP)] behave as partial agonists while the intrinsic activity of bivalent antagonists (combining two 1-NP residues) was found to be spacer dependent. Surprisingly enough, the dimer of 8-OH-DPAT 6 binds to 5HT1A, 5HT1B and 5HT1D receptors with similar high affinity.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

Dimerization of sumatriptan as an efficient way to design a potent, centrally and orally active 5-HT1B agonist.

A new bivalent ligand of formula 3 which results from the covalent coupling of two sumatriptan molecules with a p-xylyl spacer at the level of the sulfonamide nitrogen has been prepared and evaluated as a 5-HT1B/1D receptors agonist. In vitro experiments at 5-HT1B human cloned receptors (Ki = 0.64 nM; EC50 = 0.58 nM) and at the level of the contraction of the New Zealand white rabbit saphenous vein (pD2 = 6.6) demonstrate the superior potency of dimer 3 as a 5-HT1B receptor agonist when compared to sumatriptan or zolmitriptan. Interestingly enough, the new bivalent agonist 3 was found to induce hypothermia in the guineapig upon oral administration suggesting good oral activity and access to the brain.

Animals↗