No resistance. High-temperature superconductors start finding real-world uses
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Journal Article↗
Biomedical subjects
B Schechter
Publications and source records attributed to B Schechter.
Organ selective delivery using a tissue-directed streptavidin--biotin system: targeting 5-fluorouridine via TNP-streptavidin.
Trinitrophenyl (TNP) modification of streptavidin (St) resulted in high and prolonged accumulation in mouse liver following intravenous administration of radioiodinated TNP streptavidin (TNP-St). Uptake, which is correlated with increased TNP substitution, was first observed at 2-3 h, increased to 40-50% of injected dose/gram tissue (%/g) at 24 h and slowly declined later on. A low degree of accumulation (10%/g) was observed in the spleen. TNP substitution of other proteins such as bovine serum albumin (BSA) or ovalbumin (Ova) led to a transient short-term liver uptake. The enzyme-resistance property of streptavidin and its biotin binding sites render TNP-modified streptavidin a potential targeting vehicle to the liver. 5-Fluorouridine (FUR) was attached to high molecular weight carrier carboxymethyldextran (CMdex, derived from 40 kDa dextran) and the dextran FUR conjugate was charged with 2-4 biotinyl groups (in the form of biotinyl-diaminopropionyl-tyrosine, BDT) for complexing to TNP-St. Biodistribution monitoring of the BDT-CMdex-FUR ligand, radiolabeled at the tyrosyl residue of BDT and targeted via non-radiolabeled TNP-St, showed that ligand accumulation in the liver was similar to TNP-St itself. Liver targeting of FUR was demonstrated by trace-labeling FUR with its structural analog 5,6-[3H]uridine prior to conjugation to dextran hydrazide. Specific liver accumulation of [3H] radioactivity occurred following administration of the conjugate only when complexed to TNP-St. Hepatic levels of [3H] radioactivity were in the range of 25%/g or 35% per whole liver during a period of at least 8 h, as compared to the rapid elimination of free FUR+[3H]uridine (4%/g at 20 min). [3H]-drug radioactivity disappeared at a faster rate as compared to 125I-dextran radioactivity, suggesting that metabolic processes required to generate the 5,6-[3H]uracil-containing active metabolites took place.
Animals↗
Time-tested botanical remedies for modern periodontal therapy.
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Astringents↗
Immunoreactivities of polyclonal and monoclonal anti-T and anti-Tn antibodies with human carcinoma cells, grown in vitro and in a xenograft model.
Human polyclonal, monospecific anti-T and -Tn antibodies were found to be reactive in ELISA tests with human ovarian (IGROV-1, OVCAR-3 and SKOV-3), breast (SKBr-3 and T47D)- and oral (KB)-carcinoma cell lines, but less so or non-reactive with normal epithelia and fibroblasts. The direct binding radioimmunoassay, using 125I-labeled human antibodies, to the IGROV-1 cancer cells was inhibited by homologous unlabeled antibodies of the same concentration, but not by the respective immunodominant haptenic monosaccharides (Gal for T and GalNAc for Tn). Rodent ascitic monoclonal anti-T (Ca3114 and Ca3741) and anti-Tn (Ca3250, Ca3268 and Ca3638) antibodies were also reactive with the ovarian- and breast-cancer cells, as measured by FACS and ELISA tests, but to a lower extent than the polyclonal human antibodies. Both the monoclonal anti-T (Ca3741) and anti-Tn (Ca3250 and Ca3638) antibody-binding reactivities were significantly inhibited by the haptenic free monosaccharides. Addition of the above MAbs to IGROV-1 ovarian-cancer or T47D breast-cancer cells cultured in vitro resulted in significant cytological change and inhibition of the viability of the tumor cells, but not of normal epithelial breast cells. This effect on viability was shown to be complement-independent, yet it was profoundly influenced by the concentration of the serum added to the assay medium. In vivo biodistribution of the anti-T (Ca3114) and anti-Tn (Ca3638) MAbs administered i.p. to athymic IGROV-1 tumor-bearing CD1 female nude mice revealed higher 125I-labeled antibody accumulation in the tumor xenografts and in their lung tissues, as compared with other organs of the same mice tested. The above results thus suggest the feasibility of utilizing these antibodies in immunotherapy and drug targeting.
Animals↗
How the brain gets rhythm.
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Action Potentials↗
Liver accumulation of TNP-modified streptavidin and avidin: potential use for targeted radio- and chemotherapy.
Hepatic metastases of malignant tumors is a major problem in the treatment of cancers for which the liver is the most common site for recurrences. In the present study we describe a selective delivery system to the liver which may facilitate specific hepatic targeting of anti-cancer agents. Avidin and streptavidin are two biotin-binding proteins with extreme resistance to proteolytic activity. Trinitrophenyl (TNP) modification of these two proteins resulted in specific accumulation in mouse liver with levels of 40-50 percent per gram tissue (%/g) during a period of several days. The two modified proteins could target to the liver high doses of covalently bound radionuclide iodine-125, a biotinylated ligand such as biotinyl-tyrosine (BT) or large biotinylated carriers such as carboxymethyl dextran (CMdex, 40kDa). Appropriately derivatized dextrans serve as carriers for various chemotherapeutic drugs, as demonstrated here for cis-dichlorodiammineplatinum (CDDP). Specific liver targeting of CDDP complexed to CMdex-TNP-streptavidin could be monitored by flame atomic absorption spectrometry of the Pt metal: High levels of the Pt drug were concentrated in the liver for at least 15hr following its targeted delivery as compared to essentially undetectable levels after administration of the free drug.
Animals↗
Renal accumulation of streptavidin: potential use for targeted therapy to the kidney.
Streptavidin exhibits a remarkable accumulation in the kidney. Biodistribution studies with radio-iodinated streptavidin showed that 70 to 80% of the injected dose per gram tissue (%/g) were retained in kidneys of Balb/C mice for three to four days compared to less than 5%/g levels in other tissues. This observation means that 15 to 20% of the injected dose is accumulated in the kidney, an organ that constitutes less than 1% of total body weight. Similar results of percent radioactivity per total kidney were obtained in other mouse strains as well as in rats and rabbits. Avidin, or the post-secretory form of streptavidin which is of a higher molecular weight, do not show any preferential affinity to the kidney. The kidney-accumulated streptavidin was mostly confined to the cortex, concentrated in the proximal tubular cells. Accumulation of streptavidin in the kidney was independent of biotin, since addition of biotin to radio-iodinated streptavidin prior to injection did not affect its kidney uptake. Therefore, streptavidin, which aquires its kidney accumulation property following truncation of the native form, may be utilized for renal specific delivery of chemotherapeutic agents, radioactive isotopes and other effector molecules. Such ligands can be linked to streptavidin via conventional coupling methods or following their biotinylation. Preliminary experiments showed that streptavidin can target to the kidney biotinylated ligands or high doses of chemically linked radionuclides.
Animals↗
Increasing 1-beta-D-arabinofuranosylcytosine efficacy by scheduled dosing intervals based on direct measurements of bone marrow cell kinetics.
The therapeutic efficacy of cell cycle phase-specific drugs can be improved by repeated administrations, the dosing interval being related to the cell cycle time of the susceptible normal host tissue. Kinetic measurements of bone marrow cell proliferation, with bromodeoxyuridine labeling and flow cytometry analysis, were used to determine the optimal dosing intervals of 1-beta-D-arabinofuranosylcytosine for minimizing bone marrow cell damage in mice. The results showed that cells surviving a single dose 1-beta-D-arabinofuranosylcytosine treatment remained temporarily blocked at the G1-S boundary, and upon release from the block the cells crossed through S phase in a nearly synchronized way. The optimal spacing of repeated treatments, evaluated by measurements of the drug-induced transit times through the different cell cycle phases, equaled the bone marrow cell cycle time following treatment. Repeated 1-beta-D-arabinofuranosylcytosine injections according to this protocol markedly diminished drug toxicity in C3H mice, as compared to protocols of other time intervals. A therapeutic schedule based on these measurements was highly effective in lymphoma-bearing mice: the designed protocol of dosing intervals significantly delayed tumor growth whereas other intervals were highly toxic.
Animals↗
Aromatic side-chain interactions as the origin of immunological diversity in the TyrTyrGluGlu and TyrGluTyrGlu epitopes: NMR and fluorescence evidence.
Spectroscopic methods have been applied to elucidate conformational differences responsible for the immunological diversity of two synthetic multichain copolymers, Tyr1Tyr2Glu3Glu4-poly-DL-Ala--poly-Lys and Tyr1Glu2Tyr3Glu4-poly-DL-Ala--poly-Lys. Despite their far-reaching structural similarity in the epitope peptide and complete identity in the poly-Ala--poly-Lys carrier, these two copolymers manifest a wide range of opposed immunological attributes. Different genetic control mechanisms govern their immunogenic properties, and their interactions with antigen presenting cells or T cells and B cells are mediated via different immunological routes. Following previous photoCIDNP (photoChemically Induced Dynamic Nuclear Polarization) investigations, we applied NMR and fluorescence measurements to these two copolymers in order to search for structural differences that could account for their opposed immunological behaviour. The differences between the two antigens are traced to the spatial orientation of the tyrosine residues. Hydrophobic Tyr1--Tyr3 intramolecular inter-side-chain interactions characterize the Tyr1Glu2Tyr3Glu4 polymer, whereas Tyr1 and Tyr2 in the Tyr1Tyr2Glu3Glu4 polymer are non-interacting and freely rotating. It is thus inferred that Tyr1 and Tyr2 are distant and point to different directions in space, whereas Tyr1 and Tyr3 are in close proximity, as was suggested by a previous CIDNP study and by molecular structure computations. We infer that these structural differences may relate to the different immunological behaviour of the TyrTyrGluGlu and TyrGluTyrGlu polymers.
Amino Acid Sequence↗
Cytotoxicity of streptavidin-blocked biotinyl-ricin is retrieved by in vitro immunotargeting via biotinyl monoclonal antibody.
The streptavidin-biotin system has been used to immunotarget whole ricin to tumor cells in a system that overcomes ricin-nonspecific cytotoxicity. Biotin was linked to ricin via a disulfide-containing reagent, sulfosuccinimidyl-2-(biotinamido)ethyl-1,3'-dithiopropionate. The product, biotinyl-S,S-ricin (b-ricin), retained most of its in vitro cytotoxic activity against human epidermoid carcinoma (KB) cells. Complexing b-ricin to streptavidin resulted in greater than 99% loss of its cellular toxicity which is associated with loss of cell-binding activity. The streptavidin-b-ricin complex could, however, be targeted to KB cells via the biotinylated monoclonal antibody 108 which is specific to the epidermal growth factor receptor overexpressed on KB cells. The complex did not regain its activity if the specific antibody was not biotinylated or if the biotinylated antibody was of a different specificity. Streptavidin is thus used to block b-ricin, presumably due to a steric restraint of the streptavidin on the ricin B-chain, and to bridge it to biotinyl antibody recognizing the target cell. Avidin could not replace streptavidin in this system since a complex between b-ricin and avidin retained a major part (60%) of ricin cytotoxic activity. This is attributed to the nonspecific binding of avidin to cells in vitro, including the KB cells. It is suggested that b-ricin is blocked by both streptavidin and avidin, but once the complex gains access to the cell surface, its cytotoxic activity is specifically retrieved.
Avidin↗
Structural origin of the immunological diversity of two closely related tetrapeptides: CIDNP study of TyrTyrGluGlu and TyrGluTyrGlu epitopes.
Photochemically induced dynamic nuclear polarization (photoCIDNP) measurements, specific for exposed tyrosine residues, have been applied to elucidate conformational differences responsible for the immunological diversity of the synthetic multichain copolymers, Tyr1Tyr2Glu3Glu4-poly-DL-Ala-poly-Lys and Tyr1Glu2Tyr3Glu4-poly-DL-Ala-poly-LS. These two copolymers are essentially identical in their molecular weight, size, shape and composition, and differ only in the order of the two internal amino acid residues within the sequence of the tetrapeptide epitopes. Nonetheless, previous studies have shown that the two macromolecules behave differently, as evidenced by their immunological and immunogenic properties. As immunogens they act under different genetic control mechanisms, and differ in their interactions with antigen presenting cells, T cells and B cells. Antibodies elicited against these two antigens do not cross react. The photoCIDNP measurements of these two polymers, intended to elucidate discrete structural differences controlling immune recognition, showed that in the TyrTyrGluGlu polymer, Tyr1 and Tyr2 rings are free, non-interacting and undergo fast internal rotation. Computed minimum energy conformations confirm these conclusions and indicate that Tyr1 and Tyr2 point to different regions in space. In TyrGluTyrGlu, however, CIDNP measurements give rise to one broad tyrosine 3,5 proton signal, the result of a strong Tyr1-Tyr3 hydrophobic interaction. These two tyrosine residues are thus close in space, and undergo slow internal rotation. These results are in agreement with the computed minimum energy conformations.
Amino Acid Sequence↗
Effect of the dosing interval on myelotoxicity and survival in mice treated by cytarabine.
Many antineoplastic drugs are cell-cycle-phase-specific. These drugs are often highly toxic to the host, as they have the potential to impair replication, not only in the cancer cells, but also in the normal tissues. Using mathematical models it has been shown how selectivity of these drugs can be increased by exploiting the relatively large variability in cell-cycle parameters of the neoplasia. These models predict that toxicity to the host of cell-cycle-phase-specific drugs can be minimised if the dosing interval is an integer multiple of the average intermitotic interval of the susceptible host cells. Experimental evidence supporting this prediction is presented in this work. Our results show that a constant duration of the dosing interval yields higher survival rates in mice treated by cytarabine, as compared with random dosing intervals. Minimal myelotoxicity is exerted when the dosing interval is an exact multiple of the inter-mitotic time of bone marrow stem cells and erythroid progenitors (i.e. 7 h). Survival is significantly lower in mice treated every 8 h, or its multiple, as compared with that of mice treated at a 7 h or 10 h dosing interval.
Animals↗
A tale of two peptides, TyrTyrGluGlu and TyrGluTyrGlu, and their diverse immune behaviour.
Studies on a synthetic multichain polypeptide antigen, (T,G)-A--L, prepared by polymerization techniques, led to a better understanding of the molecular basis of antigenicity, and of many other immunological phenomena, as well as to the discovery of determinant-specific genetic control of immune response. In view of the intensity of studies with this polymer, we were interested in elucidating its major B and T cell epitopes. We investigated two tetrapeptides, TyrTyrGluGlu and TyrGluTyrGlu. Both were attached to multichain branched poly(DLalanine). Even though the two resulting synthetic immunogens are essentially identical in their molecular weight, size, shape and composition, and differ chemically only in the sequence of the tetrapeptide epitopes, the immunological differences observed were profound. Antibodies in the two systems do not cross-react. The major B cell epitope of (T,G)-A--L is TyrTyrGluGlu, whereas the major T cell epitope is TyrGluTyrGlu. The two antigens are under different genetic controls, and differ in their uptake by macrophages. The TyrTyrGluGlu polymer is thymus-dependent, whereas the TyrGluTyrGlu polymer is thymus-independent. Investigation of the two tetrapeptides in their polymeric form, by photochemically induced dynamic nuclear magnetic polarization techniques, shows that they differ strongly in their intra-epitope aromatic interactions. Phenolic groups in TyrGluTyrGlu interact with each other, whereas they are far apart in TyrTyrGluGlu, as seen also in computer-derived models.
Amino Acid Sequence↗
Indirect immunotargeting of cis-Pt to human epidermoid carcinoma KB using the avidin-biotin system.
Cis-diamminedichloroplatinum (II) (cis-Pt) complexed to a carboxymethyl dextran-avidin conjugate was targeted to biotin-monoclonal antibody 108 (b-MAb 108). This MAb recognizes the extracellular domain of the epidermal growth factor receptor (EGF-R) on human epidermoid carcinoma (KB) cells over-expressing EGF-R. Cis-Pt-carboxymethyl-dextran-avidin (Pt-dex-Av) containing 60-90 M cis-Pt/M avidin was administered 24 hr following b-MAb108 containing 3-5 M biotin/M MAb. This treatment was potentially more effective in suppressing the growth of established KB tumor xenografts, or in inhibiting the development of lung metastases in nude mice, than free MAb 108, free drug or MAb 108 followed by drug. Replacing b-MAb 108 by unbiotinylated antibody or by b-MAb of a different specificity also yielded lower suppressive effects. The sequential administration of Pt-dex-Av following b-MAb was more effective than introduction of the Pt-dex-Av when already complexed to b-MAb 108. The results presented in this preliminary investigation suggest that Pt-dex-Av is specifically removed from the circulation by b-MAb 108 concentrated at the tumor site.
Animals↗
Complexes and conjugates of cis-Pt for immunotargeted chemotherapy.
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Animals↗
Zidovudine toxicity to murine bone marrow may be affected by the exact frequency of drug administration.
Zidovudine (azidothymidine, AZT) toxicity to the bone marrow (BM) is a major hindrance to its widespread clinical application in the treatment of the acquired immunodeficiency syndrome (AIDS). In this work we verify the prediction of a mathematical model that cytotoxicity to the host can be reduced when the frequency of drug administration is an integer multiple of the target cell average cycle time (ca. 7 h in murine BM cells). We report in vivo experiments in mice showing that a 7-h frequency of AZT administration is significantly less toxic than other frequencies when peripheral blood parameters and the proportion of BM cells arrested at the S-phase gate of the DNA content distribution are considered.
Animals↗
Tissue distribution of avidin and streptavidin injected to mice. Effect of avidin carbohydrate, streptavidin truncation and exogenous biotin.
Radioionated avidin and streptavidin were characterized for their biodistribution and tissue association in Balb/c mice, in comparison to their interaction with cells in vitro. Binding of avidin to spleen and bone-marrow cells in vitro was up to 20-fold higher than that of streptavidin, but when tested in vivo avidin clearance from blood and tissues was considerably faster than that of streptavidin. Levels of avidin at 24 h after an intravenous injection were below 1% (of the injected dose/mass tissue) in most organs. Non-glycosylated avidin was similar in its biodistribution to native avidin. Native streptavidin exhibited higher and prolonged tissue association with 5-10% levels in lung, liver, spleen, kidney and blood, whereas its truncated form showed low tissue levels (1-3%) but a remarkably high affinity to the kidney (80%). Exogenous biotin did not affect streptavidin distribution in vivo but caused a 2-7-fold increase in the retention of avidin (but not non-glycodylated avidin) in some of the organs.
Animals↗
Blood levels and serum protein binding of cis-platinum(II) complexed to carboxymethyl-dextran.
Plasma levels and serum protein binding of cis-diamminedichloroplatinum(II) (cis-DDP) or cis-diamminediaquoplatinum(II) (cis-aq) complexed to carboxymethyl-dextran (CM-dex) with a molecular weight of 10,000 (T-10), 40,000 (T-40), and 250,000 (T-250) were investigated in BALB/c mice. Levels of active drug in the circulation after the i.v. or i.p. administration of the free or complexed drugs, as well as the loss of drug activity due to serum protein binding following incubation with mouse serum, were monitored by an antitumor in vitro assay using a drug-sensitive tumor cell line. Following i.v. injection of the complexes, active platinum(II) was maintained in the circulation at higher levels and for a longer period, whereas the free drug disappeared rapidly. The rate of disappearance of the complexed drug from the circulation was markedly influenced by the molecular size of the carrier CM-dex, since the retained amount of drug was considerably higher with the T-40 and T-250 complexes than with the T-10 complex. An i.p. injection resulted in a rapid and transient appearance of low levels of the free drugs in the blood, whereas in the case of the complexes, transport to the circulation was slower and their maintenance in the blood system was markedly higher. Serum protein binding was much slower with CM-dex-complexed drugs (regardless of the molecular size of the CM-dex carrier) than with the free drugs.
Animals↗