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Biomedical subjects

D Gaál

Publications and source records attributed to D Gaál.

At least 19 recordsLinked to original sources
PubMed2000

Synthesis and conformational studies of poly(L-lysine) based branched polypeptides with Ser and Glu/Leu in the side chains.

In a new group of polypeptides, the branches were composed of DL-Ala oligopeptide, L-serine and L-leucine or L-glutamic acid residues. The synthesis of eight different side-chain combinations is described. In the first group, Ser was attached directly to the epsilon-amino groups of polylysine, and Leu or Glu was situated at the side chain end (poly[Lys(X(i)-DL-Ala(m)-Ser(j))]). Alternatively, Leu or Glu was positioned next to the polylysine backbone (poly[Lys(Ser(j)-DL-Ala(m)-X(i))], where X=L-Leu or L-Glu and m approximately 3-6, i</=1 and j</=1). The second group of polymers was synthesised by grafting oligo(DL-alanine) chains to the epsilon-amino groups of polylysine, followed by coupling of Ser and Leu or Glu consecutively to the chain ends, however, in a different order, resulting in the polymers (poly[Lys(X(i)-Ser(j)-DL-Ala(m))] and poly[Lys(Ser(j)-X(i)-DL-Ala(m))], where X=L-Leu or L-Glu and m approximately 3-6, i</=1 and j</=1). The effect of amino-acid composition and sequence of side chains in branched polypeptides on solution conformation was studied by CD spectroscopy. CD spectra recorded in aqueous solutions of various pH (2-11) and ionic strengths (0.02-2.0 M NaCl) suggest that leucine- and serine-containing polypeptides have more ordered (alpha-helical) structure than the polymers with glutamic acid and serine residues in the same position. The influence of serine residues on ordered structure (helical or beta-sheet) formation depends on its position in the side chain as well as on the nature of amino acid X (Leu or Glu). The incorporation of Ser into the branches resulted in polypeptides possessing prolonged shelf stability and high water-solubility. No toxic effect of this new class of polymers was observed on mouse spleen cells, even after 4 h of incubation.

Animals↗
PubMed1999

Gonadotropin-releasing hormone analogue conjugates with strong selective antitumor activity.

Conjugation of gonadotropin-releasing hormone (GnRH) analogues GnRH-III, MI-1544, and MI-1892 through lysyl side chains and a tetrapeptide spacer, Gly-Phe-Leu-Gly (X) to a copolymer, poly(N-vinylpyrrolidone-co-maleic acid) (P) caused increased antiproliferative activity toward MCF-7 and MDA-MB-231 breast, PC3 and LNCaP prostate, and Ishikawa endometrial cancer cell lines in culture and against tumor development by xenografts of the breast cancer cells in immunodeficient mice. MCF-7 cells treated with P-X-1544 and P-X-1892 displayed characteristic signs of apoptosis, including vacuoles in the cytoplasm, rounding up, apoptotic bodies, bleb formation, and DNA fragmentation. Conjugates, but not free peptides, inhibited cdc25 phosphatase and caused accumulation of Ishikawa and PC3 cells in the G2/M phase of the cell cycle after 24 h at lower doses and in the G1 and G2 phases after 48 h. Since P-X-peptides appear to be internalized, the increased cytotoxicity of the conjugates is attributed to protection of peptides from proteolysis, enhanced interaction of the peptides with the GnRH receptors, and/or internalization of P-X-peptide receptor complexes so that P can exert toxic effects inside, possibly by inhibiting enzymes involved in the cell cycle. The additional specificity of P-X-peptides compared with free peptides for direct antiproliferative effects on the cancer cells but not for interactions in the pituitary indicates the therapeutic potential of the conjugates.

Animals↗
PubMed1998

Low toxicity and high antitumour activity of daunomycin by conjugation to an immunopotential amphoteric branched polypeptide.

The acid labile derivative of Daunomycin cis-aconityl Daunomycin (cAD), was coupled to an amphoteric polypeptide, poly[Lys-(Glui-DL-Alam)] (EAK), which was selected for conjugation on the basis of its pharmacological and immunological properties. The systemic toxicity of covalently attached Daunomycin was studied by monitoring body weight, life-span, bone marrow and haematological parameters of BDF1 mice. More than 3-fold the lethal dose of free Daunomycin could be applied without serious toxic effect when the drug was attached to EAK. The dose- and time-dependent modulatory effect of free drug and [cAD]-EAK conjugate on the humoral and cellular immune response to sheep red blood cell antigens in mice was studied. The conjugation of Daunomycin to EAK carrier polypeptide compensated for the immunosuppression induced by free Daunomycin. [cAD]-EAK conjugate at Daunomycin doses of 2-10 mg/kg was very effective against L1210 leukaemia producing 66-100% long-term survivors (> 60 days), while Daunomycin in itself increased the mean survival only by 52%, with no long-term survivors. The mixture of free Daunomycin and EAK polypeptide had similar toxicity and antitumour activity as free Daunomycin, indicating the important role of covalent attachment in increased therapeutic efficacy.

Animals↗
PubMed1997

Comparison of the lymphoid toxicities of mitobronitol and busulphan in mice: reduced B cell toxicity and improved thymic recovery as possible contributors to the reduced risk for complications following BMT with mitobronitol preconditioning.

It has previously been reported that the use of mitobronitol (dibromomannitol, DBM) instead of busulphan (BU) for myelosuppression is associated with significantly decreased risk for several complications of allogeneic bone marrow transplantation in accelerated chronic granulocytic leukemia. In exploring the pharmacologic basis for this observation, we have compared the acute and subacute cytotoxicities of DBM and BU on the spleen and thymus of mice. While there was comparable early (day 3) weight loss in both organs following these treatments, splenic B cells exhibited significantly less damage, and thymic regeneration (over weeks) was significantly faster following DBM treatment than with BU. These observations raise the possibility that improved post-BMT immune recovery could contribute to the clinical benefits observed with DBM-preconditioning.

Animals↗
PubMed1996

A tumor-selective somatostatin analog (TT-232) with strong in vitro and in vivo antitumor activity.

We report a series of new in vitro and in vivo data proving the selective antitumor activity of our somatostatin structural derivative, TT-232. In vitro, it inhibited the proliferation of 20 different human tumor cell lines in the range of 50-95% and induced a very strong apoptosis. In vivo TT-232 was effective on transplanted animal tumors (Colon 26, B16 melanoma, and S180 sarcoma) and on human tumor xenografts. Treatment of MDA-MB-231 human breast cancer xenografted in mice with low submaximal doses of TT-232 [0.25 and 0.5 mg/kg of body weight (b.w.)] caused an average 80% decrease in the tumor volume resulting in 30% tumor-free animals surviving for longer than 200 days. Treatment of prostate tumor (PC-3) xenografted animals with 20 mg/kg of b.w. of TT-232 for 3 weeks resulted in 60% decrease in tumor volume and 100% survival even after 60 days, while 80% of nontreated animals perished. We have demonstrated that TT-232 did not bind to the membrane preparation of rat pituitary and cortex and had no antisecretory activity. TT-232 was not toxic at a dose of 120 mg/kg of b.w. in mice. Long-term incubation (24 h) of tumor cells with TT-232 caused significant inhibition of tyrosine kinases in good correlation with the apoptosis-inducing effect. The level of p53 or KU86 did not change following TT-232 treatment, suggesting a p53-independent apoptotic effect. Preincubation of human breast cancer cells (MDA-MB-453) with TT-232 for 2 h decreased the growth factor receptor autophosphorylation. All of these data suggest that TT-232 is a promising and selective antitumor agent.

Animals↗
PubMed1996

In vivo studies of the new gonadotropin-releasing hormone antagonist--copolymer conjugates having antitumor activity.

The aim of the study was to test in vivo the gonadotropin-releasing hormone (GnRH) antagonists and their conjugates showing antitumor activities in vitro. The in vivo experiments with the human GnRH antagonist MI-1544 (Ac-D-Trp1,3,D-Cpa2,D-Lys6,D-Ala10)-GnRH, the chicken GnRH antagonist MI-1892 (Ac-D-Trp1,3,D-Cpa2,Lys5,/beta-Asp(DEA)/6,Gln8,D-Al a10)-GnRH, and their copolymer conjugates were carried out on MCF-7 and MDA-MB-231 human breast tumors xenografted in immunosuppressed CBA/Ca HRIJ-T6 female mice and on MXT mouse mammary tumors in BDF1 mice. The P-X-1544 and P-X-1892 conjugates were prepared by coupling the GnRH antagonists to macromolecule copolymer through biodegradable spacers. MI-1544 and its conjugate had strong, whereas MI-1892 and its conjugate had slight, castration effect in rats. All of them showed selective antitumor activity. The conjugates, given daily, inhibited both types of xenografts by 42 to 49%. Their activity was stronger in MXT mammary tumor (72 to 61%). The in vivo effect of GnRH antagonists was largely increased by coupling them to nonbiodegradable macromolecule carriers of polyanionic character. P-X-1544 and P-X-1892 GnRH antagonist-macromolecule conjugates might become important therapeutic agents for the treatment of breast cancer.

Animals↗
PubMed1995

Gamma scintigraphy of 111In-labelled branched chain polypeptides (BCP) with a poly(L-lysine) backbone in mice with mammary carcinoma: effect of charge on biodistribution and tumour imaging potential.

Radiolabelled synthetic branched chain polypeptides (BCP) represent a new and novel range of materials with potential as radiopharmaceuticals. Preliminary imaging studies have been undertaken with 111In-labelled BCP in mice with subcutaneously transplanted mammary carcinoma. Four polypeptides each with a poly(L-lysine) backbone and side chains of DL-alanine residues were studied. These were AK, which is polycationic, EAK which is amphoteric, having additional glutamic acid residues at the end of the side chains, and AcEAK (anionic) and SucEAK (highly polyanionic) where the terminal glutamic acid amino groups were acetylated or succinylated respectively. Radiolabelling was achieved by previous conjugation with DTPA. Serial images up to 48 hours showed marked retention of 111In-labelled polycationic AK and polyanionic SucEAK in the liver and spleen, with renal uptake also being visible in the case of AK. 111In-labelled EAK and AcEAK showed longer blood survival with some liver uptake, but tumour uptake was also visualized by 24 hours with both of these polypeptides. These studies demonstrate the feasibility of using 111In-labelled synthetic branched chain polypeptides as radiopharmaceuticals for gamma scintigraphy and the visualization of tumours by modification of the side chain structure. These materials warrant further study.

Animals↗
PubMed1993

Severe depletion of cellular thiols and glutathione-related enzymes of a carmustine-resistant L1210 strain associates with collateral sensitivity to cyclophosphamide.

Cyclophosphamide (CPA) increased the life span of both carmustine (BCNU)-resistant (L1210/BCNU) and BCNU-sensitive L1210 (L1210/0) leukaemic mice; their sensitivity to CPA, however, was extremely different. The BCNU-resistant strain was much more sensitive (collaterally) to CPA than was its sensitive counterpart. The collateral sensitivity was accompanied by a severe reduction in the activity of glutathione-related enzymes and in protein thiol (SH) and non-protein SH levels in BCNU-resistant cells. The activity of glutathione reductase (GSSG-R) was 2 times higher in the L1210/0 cells than in the L1210/BCNU cells. Glutathione-S-transferase (GST) was also almost 2 times more active in the sensitive cells than in the resistant strain. To develop resistance against CPA with a single treatment (60 mg/kg) per passage, the L1210/BCNU strain needed 26 passages, whereas the L1210/0 strain required significantly fewer. The resistance developed against CPA was associated with a moderate elevation of thiols in the L1210/CPA cells, whereas this elevation was approximately 3 times more pronounced in the L1210/BCNU/CPA cells. The severely reduced activity of GST in the L1210/BCNU strain was markedly increased when these cells were made resistant to CPA; the GSSG-R activity, however, remained low, suggesting an irreversible injury of this enzyme by BCNU.

Animals↗
PubMed1986

Inhibitory and stimulatory effects of dianhydrogalactitol, an alkylating cytostatic agent on the humoral immune response.

The effect of an alkylating agent, dianhydrogalactitol (DAG), on the humoral immune response of C57B1 mice immunized with sheep erythrocytes was studied. Different inhibitory or stimulatory effects could be achieved by varying the time and the dose of drug administration. DAG in a dose of 1.5 mg/kg given either before or after immunization induced enhanced immune responses. Higher doses (greater than 5 mg/kg) administered in the inductive phase had a marked suppressive effect while treatments at this dosage preceding immunization resulted in a stimulation. The functionally distinct cell populations acting in the immune response to sheep red blood cells are postulated to have different sensitivity to the drug.

Animals↗
PubMed1986

Immunomodulatory effect of synthetic branched polypeptides. II.

A comparative investigation of various polypeptides was carried out in order to elucidate structure-activity correlations. The immunoadjuvant properties of the chemically well-characterized branched polypeptides, poly[Lys-(DL-Alam)] (Lys:Ala = 1:2.95) (AK), poly[Lys-(D-Leui-DL-Alam)] (Lys:Ala:Leu = 1:3.0:0.95) (D-LAK), and poly[Lys-Hisi-DL-Alam)] (Lys:Ala:His = 1:2.95:0.85) (HAK), were investigated. D-LAK and HAK were able to augment the antibody response of BDF inbred mice to immunization with sheep red blood cells (SRBC), as assessed by the hemolytic plaque-forming cell assay, whereas AK had no similar effect. The stimulating effect of D-LAK and HAK was dependent on dose and timing of treatment relative to SRBC immunization. However, the optimal dose levels were lower and the effective dose interval more restricted as compared to the previously described poly[Lys-(Leui-DL-Alam)] (LAK). Like LAK, both HAK and D-LAK were able to compensate for the immunosuppressive effect of the cytotoxic drugs dianhydrogalactitol, vincristine, and 5-fluorouracil, which all have different mechanisms of action, provided that combined treatment by polypeptide and drug was applied repeatedly before the SRBC immunization.

Adjuvants, Immunologic↗
PubMed1985

Relationship between histological structure and lactate dehydrogenase isoenzyme pattern of rat mammary tumors induced by dimethylbenz(a)-anthracene.

Mammary gland tumors induced by 7,12-dimethylbenz(a)-anthracene (DMBA) in female Wistar rats could be divided into secreting and nonsecreting ones. Histological, histochemical, cytophotometric, and electron microscopic examinations yielded indirect evidence for the ab ovo malignant nature of the nonsecreting tumors but not for the secreting ones. Nonsecreting tumors showed high total lactate dehydrogenase (LDH) activity and a definite shift of the isoenzyme pattern toward isoenzymes containing M subunits compared to those of lactating mammary glands. Secreting tumors could be characterized by low total LDH activity and a moderate increase of M/H ratio. These biochemical results support the hypothesis that nonsecreting mammary tumors induced in rats--independently of metastatization and differentiation--have to be considered carcinomas while the secreting ones benign adenomas.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1984

Effects of bacterial endotoxins and their detoxified derivatives on serum and liver lipids in mice.

The influence of different endotoxins (lipopolysaccharides, LPS) obtained from Serratia marcescens 08, Escherichia coli 089, and their derivatives, detoxified either by partial hydrolysis or irradiation, on serum and hepatic lipids and on serum lipase activity in C57Black mice was studied. Endotoxic LPS elevated the serum total lipids and lipoproteins, particularly the very-low-density lipoproteins, and induced a reversible accumulation of triglycerides in the liver. Since nontoxic preparations did not cause such alterations, it is assumed that the toxicity of LPS is an essential factor in causing lipid metabolism disorder. A nearly identical increase in the lipase activity was detected in 5 to 10 hr in the sera of experimental animals treated by both toxic and nontoxic preparations. Results indicated the potential advantage of using detoxified derivatives of bacterial endotoxins in human therapy.

Animals↗
PubMed1984

Immunomodulatory effect of synthetic branched polypeptides I.

The immunomodulatory potential of poly-(Lys-[Leu-poly-DL-Ala]) (LAK) (Lys:Ala:Leu = 1:3:0.7) as the first prototype of a series of new branched polypeptides was studied. Circular dichroism spectra indicated a highly ordered structure of LAK at physiological pH. The ability of the polypeptide to stimulate antibody response to immunization with sheep red blood cells (SRBC) when applied in aqueous medium was assessed in BDF1 inbred normal mice by the hemolytic plaque-forming cell and rosette-forming cell (RFC) assays. LAK, similarly to levamisole (LEV), a clinically applied immunomodulator, stimulated the host's humoral immune response in a wide dose interval (0.02-20 mg/kg; optimal dose, 1 mg/kg); however, the number of RFC was not influenced considerably. LAK was not toxic in doses of up to 25 mg/kg. The varied timing of LAK treatment (1 mg/kg i.p.) relative to SRBC immunization resulted in an oscillating potentiation of the immune response. The immunoadjuvant activity elicited by LAK--similarly to LEV--was sufficient to produce effective compensation of immunosuppression induced by the cytotoxic drugs vincristine and dianhydrogalactitol when combined treatments on multiple schedules were applied before SRBC immunization.

Adjuvants, Immunologic↗
PubMed1978

Endogenous thymic factors regulating cell proliferation and analysis of their mechanism of action.

Endogenous factors inhibiting the proliferation of T-lymphocytes were investigated which may function as modulators of T-lymphocyte production within the thymus. An extract from calf thymus (T4) enriched in lymphocyte chalone arrests rat thymocytes at the G1 leads to S boundary and in the S phase of the cell cycle in short-term cultures. It also inhibits the proliferative response of human peripheral blood lymphocytes to PHA-P in a time-dependent manner, as well as the spontaneous proliferation of in vitro cultured human chronic leukaemic lymphoblasts. This crude extract contains two active moities which can be isolated by molecular filtration on Sephadex G-75 column. A species non-specific, cell line selectivity inhibitory effect is characteristic of the high molecular weight fraction (mol. wt. greater than 40,000). This activity is resistant to moderate heat treatment and trypsin but is sensitive to mild alkaline hydrolysis and to RNase A digestion. About ten protein components and a toluidine blue positive substance can be detected by analytical polyacrylamide gel electrophoresis. The active inhibitor, a proposed protein-RNA complex, might be identical with the chalone. The low molecular weight, non-dialysable factor (T4-4) inhibits [3H]thymidine incorporation into acid insoluble DNA in a cell non-specific manner. A possible relationship between the two activities is discussed.

Cell Division↗
PubMed1975

Effect of detergents and sucrose derivatives on the modified protein determination of Lowry.

The effect on the protein determination method of Lowry, as modified by Hartreee, of widely used detergents (sodium deoxycholate, sodium laurylsulphate, Triton X-100 and Triton WR-1339) and of sugar derivatives often used for preparing concentration gradients (sucrose, dextran, Ficoll and Metrizamide) was examined. Each of the compounds studied gave rise to a coloured product in the test; however, the correlation between concentration and optical density was usually nonlinear. The majority of these substances - especially Ficoll, Metrizamide and dextran - interfere with the procedure even at low concentrations, thus their elimination from the sample before protein determination is inevitable.

Centrifugation, Density Gradient↗