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G Laurent

Publications and source records attributed to G Laurent.

At least 145 records · Page 8Linked to original sources
PubMed1996

[Emergency angioplasty for total thrombosis of the left main coronary artery. Apropos of a case].

Complete thrombosis of the left main coronary artery is a rare angiographic finding and usually gives rise to cardiogenic shock during unstable angina or myocardial infarction. The prognosis of this condition is very dependent on the collateral coronary circulation and the myocardial protection seems to depend on the rapidity of revascularisation. Two therapeutic approaches may be envisaged; emergency coronary bypass grafting or percutaneous angioplasty, the natural history being particularly disastrous. The authors report the case of a 42-year-old patient with complete occlusion of the left main stem responsible for unstable angina and acute pulmonary oedema. The outcome with angioplasty in the acute phase associated with surgical revascularisation four days later, was good.

Angina, Unstable↗
PubMed1996

Immunodetection of apoptosis-regulating proteins in lymphomas from patients with and without human immunodeficiency virus infection.

The expression of the apoptosis-regulating genes Bcl-2, Bcl-x, Bax, Mcl-1, and p53 analyzed in 4 cases of human immunodeficiency virus (HIV)-associated Hodgkin's disease, in 36 cases of HIV-related non-Hodgkin's lymphomas (NHLs), and in 109 cases of non-HIV-related NHLs by using immunohistochemistry. HIV-associated Hodgkin's disease samples were positive for all markers. For the HIV-related NHL samples, 36, 66, 88, 100, and 94% of the cases were Bcl-2, Bcl-x, Bax, Mcl-1, and p53 were found to be expressed in 69, 65, 82, 83, and 42%, respectively. No significant differences were observed in Bax and Mcl-1 staining between HIV-unrelated NHLs of B cell and T cell types. In contrast, Bcl-2 was positive in 66/79 (83%) and 10/30 (33%) of B cell and T cell HIV-unrelated NHLs, respectively (P2 < 0.001). Peculiar patterns were observed for hairy cell leukemia (Bax+, Bcl-2+, Mcl-1-) and for anaplastic large cell lymphoma (Bax+, Mcl-1+, Bcl-2-) in HIV-unrelated NHLs. Of interest, all cases with a positive expression of Bax were also found to express either Mcl-1 and/or Bcl-2, suggesting that Mcl-1 and Bcl-2 may counteract the pro-apoptosis function of Bax in vivo by protein-protein interaction within the tumor cell, as demonstrated previously in vitro. These results suggest that apoptosis regulation may have a role in the pathogenesis of some HIV-related and HIV-unrelated NHLs.

Apoptosis↗
PubMed1996

[Symptomatic myocardial bridges. Apropos of 6 cases].

Myocardial bridge is often considered to be a simple anatomical variation often observed during coronary angiography. The responsibility of this condition for myocardial ischaemia is however uncommon and the physiopathological mechanisms are not well understood. The authors report 6 cases of myocardial bridge associated with myocardial infarction of unstable angina. The main features of this condition are discussed with respect to a review of the literature. Patients are usually young and male; the left anterior descending artery is the most commonly affected vessel: factors triggering ischaemia are discussed: coronary spasm, tachycardia and thrombosis at the site of the myocardial bridge. The diagnosis can only be made by coronary angiography showing reduction of the systolic diameter of the artery which may be accentuated by certain pharmacological tests such as injection of glyceryl trinitrate as used in the series.

Adult↗
PubMed1996

Allogeneic vs autologous stem cell transplantation vs chemotherapy in patients with acute myeloid leukemia in first remission: the BGMT 87 study.

In 204 adult patients with de novo acute myeloid leukemia (AML), we prospectively compared allogeneic bone marrow transplantation (alloBMT), autologous stem cell transplantation (ASCT) and chemotherapy (Chemo). 162 patients (79.4%) achieved a complete remission (CR). Of the 135 patients who were still in CR after consolidation, 96 patients were less than 46 years of age: 36 patients had an HLA-identical sibling donor and were allocated for alloBMT (group I); they were compared to the 60 other patients who did not have an HLA-identical sibling donor and were treated with either ASCT or chemotherapy (group II). The 3-year disease-free survival was higher for group I patients (66.5 +/- 16%) than for the 60 group II patients (42.4 +/- 13%) (P < 0.05). The actuarial risk of relapse at 3 years was significantly lower for group I patients (24 +/- 15%) than for the other 60 group II patients (56 +/- 13%; P < 0.009). By multivariate analysis, the disease-free survival and risk of relapse were influenced by the initial WBC count (P < 0.02 and P < 0.006), the number of chemotherapy courses for CR (P < 0.001 and P < 0.01) and the type of post-induction treatment (alloBMT vs no alloBMT; P < 0.1 and P < 0.02). The 99 patients who did not fulfill the inclusion criteria for alloBMT were given intensive chemotherapy including high-dose aracytine. When they were still in CR (n = 77), these patients were then randomized for either ASCT (n = 39) or Chemo (n = 38). We were unable to detect any statistical difference between ASCT and Chemo for either disease-free survival, risk of relapse or survival. These results indicate that alloBMT seems to produce results which are at least superior to those of other therapeutic modalities. The results of either ASCT or Chemo look similar.

Acute Disease↗
PubMed1995

Elementary computation of object approach by wide-field visual neuron.

An essential function of the brain is to detect threats, such as those posed by objects or predators on a collision course. A wide-field, movement-sensitive visual neuron in the brain of the locust was studied by presenting simulated approaching, receding, and translating objects. The neuron's responses could be described simply by multiplying the velocity of the image edge (dtheta/dtau) with an exponential function of the size of the object's image on the retina (e-alpha theta). Because this product peaks before the image reaches its maximum size during approach, this neuron can anticipate collision. The neuron's activity peaks approximately when the approaching object reaches a certain angular size. Because this neuron receives distinct inputs about image size and velocity, the dendritic tree of a single neuron may function as a biophysical device that can carry out a multiplication of two independent input signals.

Algorithms↗
PubMed1995

High expression of the bcl-x gene in Reed-Sternberg cells of Hodgkin's disease.

The expression of bcl-x protein, a bcl-2-related protein present in cortical thymocytes, activated lymphocytes, and plasma cells of reactive lymph nodes, was investigated in 44 cases of Hodgkin's disease (HD) in parallel with bcl-2 and Epstein-Barr virus (EBV) status. Eighty-six percent of the cases were positive for bcl-x, among them 27% with a strong signal in more than 75% of the Reed-Sternberg cells. Positivity for bcl-x was found in, respectively, 100% and 92% of the nodular sclerosis and mixed cellularity subtypes, although 4 cases of lymphocyte predominance subtype were negative. This finding was in contrast with the weaker positivity for bcl-2 staining in 44% of the cases. EBV small RNAs were detected in 43% of the cases by using in situ hybridization. Of interest, 100% of the EBV-positive samples were positive for bcl-x, whereas only 38% of these cases were bcl-2 positive. Our findings show that the bcl-x gene expression is high in HD, suggesting that bcl-x may have a role in the pathogenesis of at least some cases of HD via apoptosis regulation.

DNA, Viral↗
PubMed1995

Inhibition of lysosomal acid sphingomyelinase by agents which reverse multidrug resistance.

An increasing body of evidence appears to implicate the lipid bilayer of multidrug resistant (MDR) cells with P-glycoprotein activity. Several cationic amphiphilic drugs (CADs) have been extensively described as modulators of MDR. These same agents are also known to (1) inhibit lysosomal acid sphingomyelinase (ASmase), a phospholipid degrading enzyme, and/or (2) induce phospholipidosis in animal tissues or cultured cell lines. In this report, we randomly selected 17 CADs and evaluated their potency in modulating MDR in the murine MDR P388/ADR leukemia cell line. We compared these results with their ability to inhibit ASmase and observed a significant dose-dependent linear relationship (95% central confidence interval), between ASmase inhibition and MDR reversal. This approach permitted us to identify three new modestly potent chemosensitizers: trimipramine, desipramine, and mianserine. Modulation of MDR was not cell line specific, since CADs at 10 microM increased doxorubicin (DOX) and vinblastine (VBL) (but not methotrexate, MTX) cytotoxicity in both P388/ADR and the human MDR cell lines MES-SA/Dx5 and K562/R7, but not in the parental drug-sensitive cells. Although all chemosensitizing CADs at 10 microM significantly increased Rhodamine-123 (Rho-123) accumulation in the human leukemia MDR cell line K562/R7 and most presented significant displacement of the photoaffinity labelling probe iodoarylazidoprazosin, no correlation between these observations and the ability of CADs to sensitize MDR cells to DOX and VBL was found. In conclusion, our study strongly suggests that the chemosensitizing potency of agents such as CADs may be due to a dual mechanism of action: direct antagonism of P-gp activity and indirect modulation of P-gp activity through the disruption of cellular lipid metabolism.

Affinity Labels↗
PubMed1995

P-glycoprotein stability is affected by serum deprivation and high cell density in multidrug-resistant cells.

The control of P-glycoprotein (Pgp) expression in multidrug-resistant cells (MDR) is complex and may be regulated at different levels. We have investigated Pgp stability in four different human and hamster MDR cell lines. Using a pulse-chase procedure we show that Pgp half-life is between 14 and 17 h in all these cell lines when they are growing exponentially. However, in the presence of a low level of serum, Pgp half-life is increased four to sixfold. A similar effect is observed when the cell cultures are maintained in high cell density. The increased Pgp stability appears to be differently regulated as serum deprivation results in a general enhanced degradation of total cytoplasmic and membrane proteins. Moreover, the observed serum effect suggests the involvement of growth factors in the control of Pgp stability. These findings suggest that protein stability may be an important factor in the regulation of Pgp expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Hysteresis reduction in proprioception using presynaptic shunting inhibition.

1. The tonic responses of angular-position-sensitive afferents in the metathoracic chordotonal organ of the locust leg exhibit much hysteresis. For a given joint angle, the ratio of an afferent's tonic firing rate after extension to its firing rate after flexion (or vice versa) is typically between 1.2:1 and 3:1 but can be as large as 10:1. Spiking local interneurons, that receive direct inputs from these afferents, can, by contrast, exhibit much less hysteresis (between 1.1:1 and 1.2:1). We tested the hypothesis that presynaptic inhibitory interactions between afferent axons reduces the hysteresis of postsynaptic interneurons by acting as an automatic gain control mechanism. 2. We used two kinds of neural models to test this hypothesis: 1) an abstract nonspiking neural model in which a multiplicative, shunting term reduced the "firing rate" of the afferent and 2) a more realistic compartmental model in which shunting inhibition presynaptically attenuated the amplitude of the action potentials reaching the afferent terminals. 3. The abstract neural model demonstrated the automatic gain control capability of a network of laterally inhibited afferent units. A postsynaptic unit, which was connected to the competitive network of afferents, coded for joint angle without saturating as the strength of the afferent input increased by two orders of magnitude. This was possible because shunting inhibition exactly balanced the increase in the excitatory input. This compensatory mechanism required the sum of the excitatory and inhibitory conductances to be much larger than the leak conductance. This requirement suggested a graded weighting scheme in which the afferent recruited first (i.e., at a small joint angle) received the largest inhibition from each of the other afferents because of the lack of active neighbors, and the afferent recruited last (i.e., at a large joint angle) received the least inhibition because all the other afferents were active. 4. The compartmental model demonstrated that presynaptic shunting inhibition between afferents could decrease the average synaptic conductance caused by the afferents onto the spiking interneuron, thereby counterbalancing the afferents' large average firing rates after movements in the preferred direction. Therefore the total postsynaptic input per unit time did not differ much between the preferred and nonpreferred directions.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗
PubMed1995

Pharmacological characterization of presynaptic calcium currents underlying glutamatergic transmission in the avian auditory brainstem.

We used whole-cell patch-clamp techniques on presynaptic terminals and postsynaptic neurons of the glutamatergic magnocellularis synapse in the chick auditory brainstem to study the effects of N, P, and L-type calcium channel blockers directly on presynaptic calcium currents and transmitter release. Presynaptic calcium currents and transmitter release were unaffected by nifedipine, blocked partially by omega-agatoxin IVA and completely by omega-conotoxin GVIA. The presynaptic calcium current is a low voltage-activated, noninactivating current and its block by omega-agatoxin IVA was not reversed by repeated depolarization of the presynaptic terminal. Thus, the presynaptic calcium current that underlies transmitter release at the chick magnocellularis synapse differs in some respects from N and P-type calcium currents described in vertebrate neuronal cell bodies.

Action Potentials↗
PubMed1995

Effect of 5637-conditioned medium and recombinant cytokines on P-glycoprotein expression in a human GM-CSF-dependent leukemic myeloid cell line.

This study was aimed at evaluating the influence of 5637-conditioned medium (5637-CM) and human recombinant cytokines on both expression and function of P-glycoprotein (P-gp) in TF-1, a GM-CSF/IL-3-dependent acute myeloid leukemia cell line which constitutively expresses functional P-gp. P-gp expression was measured by flow cytometry using MRK16 monoclonal antibody. P-gp function was measured by rhodamine 123 (Rh 123) efflux kinetics. When TF-1 cells were cultured with 5637-CM (50% v/v), both P-gp expression and P-gp efflux capacity were increased in a time-dependent manner with a 4-fold increase in P-gp expression level at day 6 whereas TF-1 cell differentiation status remained unchanged as assessed by morphological studies, phenotypical and cytochemistry analysis. Recombinant cytokines including GM-CSF, G-CSF, IL-1 beta, IL-6, stem cell factor, LIF, erythropoietin, and IL-3 had no effect on P-gp expression whereas TNF alpha induced dose- and time-dependent P-gp and mdr-1 gene overexpression. However, TNF alpha-induced P-gp overexpression had no influence on P-gp efflux capacity. Furthermore, when TF-1 cells were exposed to IL-3 for periods longer than 1 month, we found that P-gp efflux capacity was increased as compared to cells cultured with GM-CSF whereas P-gp expression was unchanged. Both TNF alpha and IL-3 did not induce TF-1 differentiation. Collectively, these results suggest that cytokines may influence both expression and function of P-gp in TF-1 cells without interfering with their differentiation status. In contrast to cytokines, phorbol esters enhanced expression and efflux capacity of P-gp in parallel with TF-1 cell monocytic differentiation. Finally, our study suggests that paracrine and/or autocrine secretion of cytokines may interfere with P-gp activity in some acute myeloid leukemia cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Interdialysis blood pressure control by long haemodialysis sessions.

High blood pressure (BP) is a major factor contributing to the high incidence of cardiovascular morbidity and mortality in haemodialysis (HD) patients. According to predialysis casual BP measurements, long HD has been shown to provide good BP control. To confirm this result during the period between dialysis sessions, we performed ambulatory monitoring of BP in 91 non-selected HD patients (mean age, 58.7 (14.1) years; 14% incidence of nephrosclerosis and diabetes mellitus; treatment duration, 93.0 (77.2) months; 3 x 8 h/week, cuprophane, acetate buffer in 95% of the patients). Only one patient (1.1%) was receiving an antihypertensive medication. Ambulatory BP results were systolic (S) BP, 119.4 (19.9) mmHg; diastolic (D) BP, 70.6 (12.9) mmHg; mean (M) BP, 87.6 (13.9) mmHg. These values were significantly lower than the casual predialysis BP data and close to the reference values reported by Staessen et al. in a meta-analysis including 3476 normotensive subjects. The MBP was inversely correlated with the treatment duration, but not with interdialysis weight gain. The MBP increased significantly in the last part of the interdialysis period, and this rise was not correlated with the interdialysis weight gain. The nocturnal/diurnal ratios for SBP and DBP for the HD patients (0.97 and 0.92) were higher than the reference values reported by Staessen, (0.87 and 0.83), and argued against a nocturnal decrease in BP. We found that 52.1% of the patients had an abnormal nocturnal BP fall (MBP fall < 5%). This feature worsened during the second night of the interdialysis period.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Pressure Monitoring, Ambulatory↗
PubMed1995

Lack of correlation between expression and function of P-glycoprotein in acute myeloid leukemia cell lines.

In a panel of acute myeloblastic leukemia (AML) cell lines, representative of distinct differentiation stages, we investigated the possible correlation between drug-resistance and both expression and function of the multidrug resistance (MDR)-related P-glycoprotein (P-gp). The AML cell lines were KG1a, KG1, TF1, HEL, ML1, and two non drug-selected P-gp positive subclones originating from HL-60 (HL-60JD) and U937 (U937AQ). All these cells overexpressed the mdr1 gene (analyzed by RT-PCR) and displayed variable levels of P-gp expression. Flow cytometric semi-quantitative evaluation of P-gp with two P-gp specific monoclonal antibodies (MRK16 and UIC2) showed the following P-gp expression hierarchy: TF1 < KG1a < HEL < KG1 < HL-60JD < ML1 < U937AQ; the latter expressing 13 times more P-gp than TF1. When P-gp function was assessed by Rhodamine 123 (Rh123) efflux kinetics, we found that only KG1a and KG1 cells, which have an early (immature) CD34+ CD33- CD38- phenotype, and to a lesser extent TF1, with an intermediate (CD34+ CD33+ CD38+) phenotype, displayed significant P-gp activity which could be inhibited by both verapamil and SDZ PSC 833. In contrast, the other more mature CD33+ CD34- AML cell lines presented no Rh123 efflux capacity although they expressed higher P-gp levels. Daunorubicin (DNR) accumulation studies showed that inhibitors of P-gp increased DNR accumulation only in the immature AML cells whereas they had no impact on the mature AML cell lines. MTT drug cytotoxicity assay confirmed that the immature AML cells were 10-15-fold more resistant to DNR than the mature AML cells. Although P-gp inhibitors were able to increase the cytotoxicity of DNR in AML cells which displayed functional P-gp, they could not increase DNR cytotoxicity to levels comparable to that of the CD34- CD33+ cells, suggesting that DNR resistance of immature AML cells may not solely be related to P-gp. With drug-selection, AML subclones displayed higher levels of P-gp expression and higher extruding capacities, and therefore chemoresistance, and this independently of their initial differentiation phenotype. Finally, this study provides evidence for a lack of correlation between expression and function of P-gp in AML cells; this relationship being dependent upon leukemic cell differentiation in unselected myeloid leukemic cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Evidence for transcriptional control of human mdr1 gene expression by verapamil in multidrug-resistant leukemic cells.

We investigated the mechanism of verapamil (VRP) effects on mdr1 gene expression in two leukemic multidrug-resistant (MDR) cell lines, K562/ADR and CEM VLB100. Exposure to VRP for 24 hr resulted in a decrease in mdr1 mRNA levels that was dose related at concentrations between 15 and 50 microM. The maximal decrease of mdr1 mRNA levels was found to be 6-fold in the K562/ADR cells and 3-fold in the CEM VLB100 cells. The effect of VRP on mdr1 mRNA levels was, however, biphasic. At 100 microM VRP, which strongly inhibited cell proliferation, a 2-fold increase of mdr1 mRNA levels was observed in the K562/ADR cells. To determine whether the decrease of mRNA levels resulted from post-transcriptional mechanisms, mRNA stability was studied after blocking of transcription with actinomycin D in VRP-treated cells and in control cells. This study revealed that mdr1 mRNA was stable in both cell lines and no increase in mdr1 mRNA degradation was observed in the 30 microM VRP-treated cells versus control cells (half-lives of 23 hr versus 14 hr for the K562/ADR cells and 15.5 hr versus 10.0 hr for the CEM VLB100 cells). The suggestion of a transcriptional mechanism was confirmed by nuclear run-on assays. A 4-fold decrease in the mdr1 gene transcription rate was observed in the 30 microM VRP-treated CEM VLB100 cells. The decreased transcription rate could be due to the decrease in mdr1 proximal promoter activity observed in CEM VLB100 cells transiently transfected with the mdr1 promoter fused to the chloramphenicol acetyltransferase gene. Indeed, after exposure to 30 microM VRP, chloramphenicol acetyltransferase activity was decreased by 2-fold. This study reports for the first time a down-regulation of mdr1 gene transcription by a pharmacological agent. These results provide further identification of the regulatory mechanisms involved in the overexpression of mdr1 in MDR cells and may help in the development of new strategies for MDR reversal.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Effect of the protein kinase C inhibitor staurosporine on chemosensitivity to daunorubicin of normal and leukemic fresh myeloid cells.

The effect of the protein kinase C (PKC) inhibitor staurosporine (ST) on the chemosensitivity of normal (colony-forming unit granulocyte-macrophage [CFU-GM]) and leukemic (acute myeloid leukemia-CFU [AML-CFU]) myeloid progenitors to daunorubicin (DNR) was evaluated. Primary colony inhibition assays allowed us to characterize two distinct groups of AML, a DNR-resistant group (patients no. 1 through 6), which displayed significantly lower DNR sensitivity than normal CFU-GM (D50 = 11.3 +/- 1.4 ng/mL v 1.8 +/- 0.5 ng/mL, after 7 days of exposure, respectively; P < 0.01) and a DNR-sensitive group (patients no. 7 through 12) with D50 = 2.7 +/- 0.4 ng/mL. This classification remained unaltered when assessed by secondary colony inhibition assay (evaluating the self-renewal fraction of AML-CFU) or by viability assay (evaluating the ultimately differentiated blast cell population), suggesting that the DNR sensitivity profile in maintained throughout AML-CFU differentiation. DNR resistance of the differentiated blast cell population was not correlated with the level of P-glycoprotein (P-gp) expression but rather with the ability to extrude rhodamine 123 (Rh123). ST used at subtoxic concentrations induced a twofold to threefold enhancement of DNR cytotoxicity, increased Rh123 accumulation, and decreased Rh123 efflux kinetics in resistant AML cells. These effects were observed for ST concentrations much lower than those required to displace the P-gp-binding probe azidoprazosin, suggesting that ST might act through its PKC inhibitory effect and not through P-gp binding. Finally, this study provides evidence that DNR resistance in AML cells is, at least in part, related to the multidrug-resistance (MDR) phenotype. Because P-gp function can be downregulated by ST, it seems likely that the MDR pheno-type can be functionally regulated by cellular signalization in AML cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Verapamil decreases P-glycoprotein expression in multidrug-resistant human leukemic cell lines.

We studied the effect of verapamil on Pgp expression (Pgp) in MDR human leukemia cell lines, K562/ADR and CEM VLB100. In the K562/ADR cell line, addition of verapamil to the culture medium (15 microM concentration) resulted in a 3-fold decrease in Pgp expression after 72 hr exposure. The effect of verapamil was reversible, and Pgp expression reached the level of untreated controls 24 hr after discontinuation of verapamil. Similar results were obtained with the human vinblastine-resistant cell line, CEM VLB100. On the contrary, no effect on Pgp expression was observed when the cells were treated with nifedipine or diltiazem (2 other calcium-channel blockers), even at doses that inhibited cell proliferation. The level of Pgp mRNA in the presence of verapamil was measured by Northern blot and was also decreased 2-fold (with the maximum reached within 24 hr), suggesting a transcriptional or post-transcriptional mechanism for verapamil. We further established that the effect of verapamil on Pgp expression led to an increase in DNR and VLB accumulation and cytotoxicity. These results suggest that verapamil acts specifically on Pgp expression in these drug-selected leukemic cells. The identification of a potentially novel mechanism of action may provide new insights as to how chemosensitization may be more effectively applied in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Cyclosporin A and cyclosporin SDZ PSC 833 enhance anti-CD5 ricin A-chain immunotoxins in human leukemic T cells.

Recent studies have shown that cyclosporin A (CsA) may affect ricin A-chain immunotoxin (RTA-IT) therapy. In this study, we evaluated the ability of CsA and its nonimmunosuppressive analog, SDZ PSC 833, to enhance anti-CD5 T101 RTA-ITs in vitro. Both 4 mumol/L CsA and 4 mumol/L SDZ PSC 833 significantly and specifically enhanced the cytotoxic activity of T101 RTA-IT on the human lymphoblastic T-cell line, CEM III (101-fold and 105-fold, respectively). Furthermore, these Cs also enhanced the cytotoxicity of the more potent T101 F(ab')2 RTA-IT (ninefold and eightfold, respectively). The effect of human plasma, originating from four patients enrolled in a phase I high-dose CsA regimen, was examined on T101 RTA-IT cytotoxicity on CEM III cells. In each case, with plasma CsA levels between 3,090 and 4,860 ng/mL (2.5 to 4 mumol/L), a significant increase in T101 RTA-IT-mediated cytotoxicity was observed ranging from 31% to 60%. Neither CsA nor SDZ PSC 833 affected the rate of RTA-IT binding, internalization, intracellular trafficking, or degradation. Analysis of internalized T101 RTA-IT molecules showed that these were essentially intact, which suggests that these enhancers may act only on a small population of RTA-ITs that escapes present investigational techniques. In conclusion, because the concentrations used are clinically achievable, Cs appear to be promising agents for in vivo enhancement of RTA-ITs.

Antigens, CD↗