Working through centred on the body in the analysis of a psychotic adolescent.

Through a few clinical sessions, the author demonstrates the complexity of psychoanalytic work with difficult adolescents, while also indicating its benefits when this approach is enhanced by working on the body-mind connection. The author shows how she establishes contact with a difficult adolescent patient who is experiencing immense fear and intense hatred of her body and how this patient then communicates through her body intense anxieties relating to body-mind dissociation. The bodily transference is central to this work.

The antiangiogenic agent neovastat (AE-941) inhibits vascular endothelial growth factor-mediated biological effects.

Purpose: Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis, which exerts direct effects on vascular endothelial cells, including endothelial cell proliferation and survival, tubulogenesis, and vascular permeability. In this study, we examined whether Neovastat, a naturally occurring multifunctional antiangiogenic drug, could inhibit the endothelial cell response to VEGF stimulation.

Results: We demonstrated that Neovastat was able to block the VEGF-dependent microvessel sprouting from Matrigel-embedded rat aortic rings, and it also blocked the VEGF-induced endothelial cell tubulogenesis in vitro.

Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials.

Recent studies have indicated that bone marrow angiogenesis is increased in multiple myeloma, suggesting that treatment with an antiangiogenic agent might be useful. Among the new antiangiogenic drugs in development, Neovastat (AE-941; Aeterna Laboratories, Quebec City, Canada) can be classified as a naturally occurring multifunctional antiangiogenic agent. It has a marked inhibitory effect on the formation of blood vessels in the chicken embryo vascularization assay (EVT) and endothelial cell proliferation.

Microtubule disruption induced in vivo by alkylation of beta-tubulin by 1-aryl-3-(2-chloroethyl)ureas, a novel class of soft alkylating agents.

We have previously reported that 4-tert-butyl-[3-(2-chloroethyl)ureido] benzene (4-tBCEU), a potent cytotoxic agent, modulates the synthesis of tubulins, suggesting that its cytotoxicity may be mediated through an antimicrotubule mechanism. Indeed, 4-tBCEU and its 4-iso-propyl (4-isopropyl [3-(2-chloroethyl)ureido] benzene) and 4-sec-butyl (4-sec-butyl [3-(2-chloroethyl)ureido] benzene) homologues induced disruption of the cytoskeleton and arrest of the cell cycle in G2 transition and mitosis. To better understand the mechanisms responsible for microtubule disruption by 1-aryl-3-(2-chloroethyl)ureas (CEU), we first examined their cytotoxicity on Chinese hamster ovary cells resistant to vinblastine and colchicine due to the expression of mutated tubulins (CHO-VV 3-2).

Interaction between lipid bilayers and a new class of antineoplastic agents derived from arylchloroethylurea: a 2H solid-state NMR study.

We have investigated the interaction between a new class of antineoplastic agents derived from arylchloroethylurea (CEU) and model membrane of dimyristoylphosphatidylcholine by deuterium nuclear magnetic resonance spectroscopy. The results indicate that the drug incorporates in the bilayer and causes an increase of the lipid acyl chain order, this effect being greater close to the interfacial region of the lipid bilayer. The increase in ordering is dependent on the nature (degree of ramification, length of the alkyl chain, and presence of a sulfur atom) as well as on the position of the R substituent and is correlated with the cytotoxicity of the drugs.

Down-regulation of interleukin-1beta production and PGE2 accumulation by an indomethacin-phenylalanine derivative in human monocytes.

This study was initiated to investigate the mechanism of action of a new indomethacin derivative, indomethacin-phenylalanine (indo-Phe) in human monocytes. We determined the effect of indo-Phe on the induction by LPS of prostaglandin-E2 (PGE2) and interleukin-1beta (IL-1beta) production in human monocytes. Indomethacin and indo-Phe inhibited the PGE2 synthesis in treated and untreated IL-1beta or LPS-treated monocytes.

Nanoerythrosomes, a new derivative of erythrocyte ghost: III. Is phagocytosis involved in the mechanism of action?

We have previously developed a new drug carrier, named nanoerythrosome which is prepared by extrusion of erythrocyte ghosts to produce small vesicles having an average diameter of 100 nm. Daunorubicin (DNR) conjugated to these nanoerythrosomes has a higher antineoplastic index than the free drug. Moreover, since nanoerythrosomes are particles, phagocytosis may be involved in their mechanism of potentiation.

Interaction of 4-tert-butyl-[3-(2-chloroethyl) ureido] benzene with phosphatidylcholine bilayers: a differential scanning calorimetry and infrared spectroscopy study.

We have investigated the interaction between a new antineoplastic drug, 4-tert-butyl-[3-(2-chloroethyl)ureido] benzene (tBCEU), and distearoylphosphatidylcholine bilayers using differential scanning calorimetry, Fourier transform infrared spectroscopy (FT-IR), and high-pressure infrared spectroscopy. The results obtained with the three different techniques indicate that the drug incorporates in the lipid bilayer. More specifically, the incorporation of the tBCEU results in a decrease in the phase transition temperature of the lipid and in an increase in the amount of gauche conformers in the liquid-crystalline phase.

Nanoerythrosomes, a new derivative of erythrocyte ghost II: identification of the mechanism of action.

We have recently developed a new drug which is a carrier from red blood cell membrane. This carrier, named nanoerythrosome (nEryt), is prepared by extrusion of erythrocyte ghosts to produce small vesicles having an average diameter of 100 nm. Daunorubicin (DNR) was covalently conjugated to the nEryt (nEryt-DNR) using glutaraldehyde as homobifunctional linking arm.

Nanoerythrosome, a new derivative of erythrocyte ghost: preparation and antineoplastic potential as drug carrier for daunorubicin.

Liposomes and monoclonal antibodies are used as drug carriers for the optimal delivery of pharmacologic agents. However, they present disadvantages that led us to develop a new model of drug carriers: the nanoerythrosomes. Nanoerythrosomes are vesicles prepared by the extrusion of red blood cell ghosts, the average diameter of these vesicles is 0.

Control of the expression of thrombospondin 1 in human breast cancer cell lines.

Thrombospondins (TSP) are adhesive glycoproteins which are synthesized, secreted and incorporated into the extracellular matrix of a variety of cells, including mammary epithelial cells. These molecules are included in a gene family that is composed of at least four members. Their roles in the mammary gland are associated with two contradictory functions: antiangiogenesis and tumor invasiveness.

Lack of cross-resistance to a new cytotoxic arylchloroethyl urea in various drug-resistant tumor cells.

1-Aryl 3-(2-chloroethyl) ureas (CEUs), a new class of potent antineoplastic agents, were recently developed in our laboratory. These compounds were designed from the aromatic moiety of chlorambucil and the unnitrosated pharmacophore of carmustine. In the present study we investigated the effect of the potent CEU derivative 4-tert-butyl-[3-(2-chloroethyl)ureido] benzene (tBCEU) on tumor cell lines selected for resistance to a wide range of anticancer drugs.

Effect of an aryl chloroethyl urea on tubulin and vimentin syntheses in a human breast cancer cell line.

A new class of antineoplastic agents, 1-aryl-3-(2-chloroethyl) ureas (CEUs), was recently developed in our laboratory. To optimize the pharmacological and the biological properties of this new class of compounds and to determine its mechanism of action, at the cellular level, we studied the effect of 4-tert-butyl-[3-(2-chloroethyl) ureido] benzene (tBCEU) on MDA-MB-231, a human breast cancer hormone-independent cell line. The effect of tBCEU on protein synthesis and on the accumulation of specific mRNAs was evaluated.

Differential effects of the simian virus 40 early genes on mammary epithelial cell growth, morphology, and gene expression.

To study the effect of SV40 T-antigen in mammary epithelial cells, a rat beta-casein promoter-driven SV40 early-region construct was stably introduced into the clonal mouse mammary epithelial cell line HC11. With the expression of the viral T-antigens under the control of a hormone-inducible promoter, it was possible to dissociate the effects of different levels of T-antigen expression on cell growth, morphology, and gene expression. Following hormonal induction, a rapid but transient induction of T-antigen was observed, followed by a delayed induction of H4 histone mRNA.

Cell and species distribution of prolactin-inducible annexin I mRNA.

The major prolactin-induced gene in the Columbid cropsac (cp35) is a unique member of the annexin (lipocortin/calpactin) gene family, most closely related to mammalian annexin I. Because no other annexins are known to be regulated by a specific hormonal signal, we have analyzed the distribution of annexin I mRNAs which hybridize to cp35 cDNA by comparing several tissue and cell systems. In addition we have used in situ hybridization to locate the expression of cp35 mRNA in the cropsac.

Beta-adrenergic receptors in the rat mammary gland during pregnancy and lactation: characterization, distribution, and coupling to adenylate cyclase.

To investigate a possible role of catecholamines in mammary gland growth and differentiation, we have studied the characteristics of a specific beta-adrenergic receptor population during the different reproductive phases of the rat mammary gland, namely pregnancy and lactation. The functional response to mammary beta-adrenergic receptor stimulation was assessed by measurement of adenylate cyclase activity during the same physiological states of the gland [125I]Cyanopindolol (CYP) binds specifically to membranes prepared from lactating mammary glands. Scatchard analysis of the binding data shows the presence of a single class of high affinity sites, with an apparent Kd value of 25.

Hormone-dependent beta-casein mRNA stabilization requires ongoing protein synthesis.

The role of ongoing protein synthesis in mediating the posttranscriptional effects of hormones on casein gene expression in the COMMA D mouse mammary epithelial cell line was investigated using the protein synthesis inhibitors, cycloheximide and anisomycin. When COMMA D cells were pretreated with insulin and PRL for 24 h, the addition of glucocorticoids induced a greater than 20-fold increase in beta-casein mRNA accumulation with an apparent lag of greater than 8 h. Addition of cycloheximide and anisomycin not only prevented this increase, but unexpectedly, resulted in the rapid disappearance of preexisting beta-casein mRNA with a half-life of approximately 2 h.

Beta-adrenergic receptors in DMBA-induced rat mammary tumors: correlation with progesterone receptor and tumor growth.

In order to gain further knowledge about the potential role of catecholamines in mammary carcinoma, we have used the potent beta-adrenergic antagonist cyanopindolol (CYP) as iodinated ligand to characterize beta-adrenergic receptors in membranes prepared from mammary tumors induced by dimethylbenz(a)anthracene (DMBA) administration in the rat. The binding of [125I]CYP to membrane preparations of DMBA-induced rat mammary tumors is rapid at room temperature, reaching half maximal specific binding at 30 min of incubation. Scatchard analysis of the data indicates that [125I]CYP binds to a single class of high affinity sites (114 +/- 2.

Androgens modulate epidermal growth factor receptor levels in the rat ventral prostate.

In order to further understand the factors which influence the normal or pathologic growth of the prostate, we have characterized the receptor for epidermal growth factor (EGF) in the rat ventral prostate and have studied the hormonal regulation in this receptor. EGF binds to a single class of saturable, high affinity binding sites in total prostatic homogenate. Scatchard analysis of the binding data reveals an apparent dissociation constant (KD) of 0.

Characterization of beta-adrenergic receptors in dispersed rat testicular interstitial cells.

Recent studies have shown that beta-adrenergic agents stimulate steroidogenesis and cyclic AMP formation in mouse Leydig cells in culture. To obtain information about the possible presence and the characteristics of a beta-adrenergic receptor in rat testicular interstitial cells, the potent beta-adrenergic antagonist [125I]cyanopindolol (CYP) was used as ligand. Interstitial cells prepared by collagenase dispersion from rat testis were incubated with the ligand for 2 h at room temperature.

Characteristics of the beta-adrenergic receptor in the rat ventral prostate using [125I]cyanopindolol.

The binding characteristics of the beta-adrenergic receptor in the rat ventral prostate homogenate have been studied using the highly potent beta-adrenergic antagonist [125I]cyanopindolol (CYP) as ligand. The bound ligand was separated from the free moiety by precipitation with polyethylene glycol (PEG-6000). This technique is simple, accurate, fast and more advantageous than filtration of the hormone-receptor complex on glass fiber filters or direct centrifugation.

Radioautographic localization of beta-adrenergic receptors in the rat ventral prostate.

Previous studies performed with crude homogenates have demonstrated the presence of beta-adrenergic receptors in the rat ventral prostate. The precise localization of these receptors in prostatic tissue, however, has not been determined. The present study describes the localization of beta-adrenergic receptors using in vitro radioautography.

Characteristics of the beta-adrenergic stimulation of adenylate cyclase activity in rat ventral prostate and its modulation by androgens.

Beta-adrenergic agents cause a 2.5-3-fold stimulation of adenylate cyclase activity in rat ventral prostate membrane preparations with an order of potency (KD values) typical of a beta 2-subtype receptor: (-)isoproterenol (20 nM) greater than (-)epinephrine (70 nM) much greater than (-)norepinephrine (1 microM) much greater than dopamine (70 microM). The stimulatory effect exerted by high concentrations of dopamine (greater than 0.

Comparison of the antiandrogenic/androgenic activities of flutamide, cyproterone acetate and megestrol acetate.

Flutamide is approximately 2-fold more potent than cyproterone acetate in reversing the stimulatory effect of dihydrotestosterone (DHT) on ventral prostate weight. Even at the highest dose of cyproterone acetate, prostate weight remains 40% above control while flutamide completely reverses the stimulatory action of DHT, thus suggesting some partial androgenic activity of cyproterone acetate. Megestrol acetate, on the other hand, is devoid of any antiandrogenic activity and it even increases the stimulatory effect of DHT on prostate weight.