Biomedical subjects

I Rabinovitz

Publications and source records attributed to I Rabinovitz.

24 records · Page 2Linked to original sources

PubMed1995

The alpha 6 beta 1 and alpha 6 beta 4 integrins in human prostate cancer progression.

Prostatic secretions are formed by glands composed of basal and luminal cells and surrounded by a basal lamina. The normal basal cells express several integrins (extracellular matrix receptors) including alpha 2, 3, 4, 5, 6, v, beta 1 and beta 4. These integrin units are polarized at the base of the cells adjacent to the basal lamina. The integrin alpha 6 beta 4 is associated with hemidesmosomal-like structures. The natural history of prostate cancer involves the presence of prostatic intraepithelial neoplasia (PIN) lesions (considered precursor lesions), carcinoma in situ and invasive carcinoma. Hemidesmosomal proteins and the alpha 3 beta 1 and alpha 6 beta 1 integrins (laminin receptors) are retained in the early PIN lesions. Expression of the integrins alpha 2, alpha 4, alpha 5, alpha v and beta 4 is lost in carcinoma. The alpha 3 beta 1 and alpha 6 beta 1 integrins remain associated with invasive carcinoma, the latter being predominant. Integrin expression in carcinoma is diffuse in the plasma membrane and not restricted to the basal aspects of the cell. The alpha 6 beta 1 integrin is fully functional as judged by an ability to adhere to laminin and contains the wild type alpha 6A cytoplasmic signaling domain. The alpha 6 beta 1 integrin is a leading candidate for conferring the invasive phenotype in prostatic carcinoma. Tumor cells with high expression of alpha 6 integrin are more invasive when tested in a SCID mouse model system. Following intraperitoneal injection, the human tumor cells invade the mouse diaphragm and move through the muscle on the surface of the laminin coated muscle cells. Our current working hypothesis is that the production of alpha 6 beta 1 and laminin in human tumor cells contributes to the invasive phenotype. Invasion could occur on the surfaces of laminin coated structures such as the nerves, blood vessels or muscle and account for the known patterns of human prostate tumor progression. Blockage of the expression or function of alpha 6 beta 1 or laminin or preventing the loss of beta 4 would be essential steps in confining the carcinoma to the prostate gland where conventional treatment has already proven effective.

Amino Acid Sequence↗

PubMed1994

Biosynthesis and secretion of laminin and S-laminin by human prostate carcinoma cell lines.

Laminin has been previously shown to participate in tumor invasion and metastasis. Tumorigenesis by human prostate cell lines can be influenced by exogenous laminin. We have found that the human prostate tumor cell lines DU145, LNCaP, and PC-3 produce a variant form of the B1 chain of laminin, known as S-laminin. DU145 cells produce laminin containing a ratio of A:B1:B2:S of 1.8:1.0:2.5:1.0, respectively, compared to LNCaP cells, which have a ratio of A:B1:B2:S of 1.0:0:10.0:2.5. Kinetic analysis of laminin production showed that LNCaP cells retained most of their laminin production and secreted laminin forms characterized by decreased levels of n-acetyl glucosamine and sialic acid. In contrast, DU145 cells secreted most of their laminin in mature forms. LNCaP cells bound very little laminin to their surface. These features of LNCaP cells could contribute to their documented low adhesivity in vitro and its nontumorigenic phenotype.

Glycosylation↗

PubMed1993

Characterization of integrin subunits, cellular adhesion and tumorgenicity of four human prostate cell lines.

Cellular adhesion to extracellular matrix proteins via integrin molecules is a major factor in the process of invasion and metastasis of human tumor cells. Four human prostate cell lines were characterized according to the presence and quantity of integrin subunits, the ability of the cells to attach to extracellular substrates and the capacity of the cells to form tumors in severe combined immunodeficient (SCID) mice. All four human prostate cell lines expressed three to five integrins on their cell surfaces. The DU145, PC3 and 431P cells expressed primarily alpha 3, alpha 5, and alpha 6 integrin at similar levels. These cell lines expressed the subunits beta 1, beta 3, and beta 4 with beta 1 predominant. The DU145 cells preferred attachment to fibronectin, followed by laminin and vitronectin. Approximately 50%-60% of the binding of DU145 cells to fibronectin and laminin was dependent on the function of alpha 5 beta 1 and alpha 6 respectively. The cell line LNCaP differed in its low expression of the alpha 3 subunit, 95% of cellular adhesion to fibronectin and laminin being integrin-dependent and its inability to attach to vitronectin, in spite of surface expression of alpha v beta 3. All the cell lines except for LNCaP readily formed tumors within SCID mice and the expression of alpha 3, alpha 6, beta 1 and beta 4 integrin subunits was preserved in the resulting tumor tissue. The altered adhesion properties of the LNCaP cells may explain their altered tumorigenicity.

Animals↗

PubMedDate not supplied

Protection and inflammatory markers following exposure of guinea pigs to sarin vapour: comparative efficacy of three oximes.

The purpose of the present study was to compare the antidotal efficacy and the combined effects on inflammatory markers of three oximes--toxogonine, TMB4 and 2-PAM--in combination with anticholinergic drugs following exposure to sarin vapour by inhalation. Guinea pigs restrained in plethysmographs were exposed to various doses of sarin vapour (in the range of 1.4-4.4LD50). The antidotal mixture was injected immediately (5-20 s) following exposure (3 mg kg(-1) atropine and 1 mg kg(-1) benactyzine in combination with 6 mg kg(-1) toxogonine, 2 mg kg(-1) TMB4 or 12 mg kg(-1) 2-PAM). Bronchoalveolar lavage (BAL) samples were taken from surviving animals 24 h after exposure to determine the levels of inflammatory markers. A differential cell count was performed in BAL samples on Giemsa-stained slides. The inflammatory markers--histamine and prostaglandins (PGE)--were measured in BAL using radioimmunoassay (RIA) techniques. The survival rate in the various treatment groups and analysis of BAL samples showed that: (i) Toxogonine, TMB4 and 2-PAM, without pyridostigmine pretreatment, at doses that were proportional to their doses in the respective auto-injectors, exhibited similar antidotal efficacy against sarin exposure. (ii) The results demonstrated that a centrally acting anticholinergic drug is essential in the antidotal mixture to ensure survival. (iii) Histamine release and eosinophilia following sarin inhalation might require additional intervention, aimed at reducing the symptoms of allergic reaction and possibly expediting recovery.

Animals↗

PubMedDate not supplied

Determination of therapeutic doses of bisquaternary oximes in large animals.

This report presents a non-lethal method for estimating a range of therapeutic doses of bisquaternary oximes that serve as antidotes against organophosphorus poisoning. We have estimated therapeutic oxime doses that are equivalent in their relative toxicity rather than selecting arbitrary fractions of their LD(50). Thus, toxic signs of the oximes HI-6, HLö-7, Toxogonin, AB-8 and AB-13 were monitored quantitatively in baboon monkeys and beagle dogs. Using Toxogonin as a reference oxime, a calculated unit of equivalent dose (CED) was defined as the oxime dose equal to the ratio between its minimal toxic dose (MTD) and the therapeutic ratio (TR) of Toxogonin i.e. CED = MTD/TR. Assuming that the tails of dose-response curves of toxicity for bisquaternary oximes are shallow and similar to one another, one could substitute the ED(10) for the MTD. The ED(10) values for bisquaternary oximes were estimated using the log-log model following experimental observations and quantitative scoring of toxic signs in dogs and monkeys. The MTD values then were calculated using the ED(10) values and the experimental therapeutic dose of the reference oxime Toxogonin. The following CED values were obtained for AB-8, AB-13, Toxogonin, HI-6 and HLö-7 in dogs (d) and monkeys (m): 98.7, 74.2, 30.0, 14.5 and 12.1 (d) and 281.9, 232.1, 41.7, 192.9 and 92.9 (m) micromol kg(-1), respectively. The antidotal efficacy of these oximes against poisoning by the nerve agent tabun was determined in dogs and monkeys. These dose-dependent efficacy data were obtained at 0.3 x CED, 1 x CED and 3 x CED of oximes in combination with atropine. These data provide comparative therapeutic values using oxime doses based on their relative toxicity. The highest antidotal efficacy against tabun in dogs was obtained for toxogonin, whereas HLö-7 and AB-13 were most efficacious in monkeys.

Animals↗

PubMedDate not supplied

Degradation of VX and sulfur mustard by enzymatic haloperoxidation.

Chloroperoxidase (CPO) isolated from Caldariomyces fumago (20 U ml(-1)) together with urea hydrogenperoxide (UPER, 0.5 mM) and sodium chloride as co-substrate (NaCl, 0.5 M) caused rapid breakdown of VX (10 microM) (t((1/2)) = 8 s, 25 C, 50 mM tartarate, pH 2.75). Glucose oxidase (GOX, Aspergillus niger) and glucose were used as an alternative source for H(2)O(2). A mixture of GOX (20 U ml(-1)), glucose (GLU 0.45 M), CPO (20 U ml(-1)) and NaCl (0.5 M) caused a 3.8-fold slower degradation of VX (10 microM) (t((1/2)) = 30 s, 25 C, 50 mM tartarate, pH 2.75). The concentrations of H(2)O(2) and chlorine produced by this enzyme/substrate mixture depended mainly on the GLU concentration. Horseradish peroxidase (HRP) together with UPER (1 mM) and sodium iodide (NaI, 0.05 M) caused progressive degradation of VX that was more than 400-fold slower than with CPO (20 U ml(-1)), UPER (0.5 mM) and NaCl (0.5 M) (t((1/2)) = 55 min, 25 C, pH 8). Skin decontamination of VX by CPO was tested in pig-ear skin in vitro. The chemical agent VX (0.01 M, 100 microl) was degraded by 98% within 3 h of skin diffusion when a mixture of UPER/NaCl/CPO was applied 60 min prior to VX application. A mixture of UPER/NaCl without CPO also caused significant VX degradation (94%) during skin diffusion whereas it did not cause any VX degradation in solution. Degradation of VX in skin, obtained without exogenous CPO, may indicate involvement of endogenous intradermal haloperoxidase-like enzyme. Reagent UPER (1 mM) did not cause any degradation of VX in solution or during its skin diffusion. Furthermore, a mixture of CPO, UPER and NaCl caused rapid degradation of sulfur mustard (HD). Sulfur mustard (50 microM) incubated in the presence of CPO (4 U ml(-1)), UPER (0.05 M) and NaCl (0.5 M) at pH 2.75 and 30 C was oxidized by 97% and 99% within 5 and 10 min, respectively. The oxidation products HD sulfoxide, HD sulfone and HD sulfoxidevinyl were identified by GC/MS in the enzymatic chloroperoxidation mixture.

Animals↗