Higher Antitumor Efficacy of Daunomycin When Linked to Dextran: In Vivo and In Vitro Studies
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Bernstein, Alon; Hurwitz, Esther; Maron, Ruth; Arnon, Ruth; Sela, Michael; Wilchek, Meir

doi:10.1093/jnci/60.2.379

Cited by 118 publications

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“…As can be seen in Fig. 3, even daunomycin-dextran uncoupled to antibodies was more effective than the free drug, most probably due to its lower toxicity (21,22). It is of interest that when the treatments were given by a different route than the tumor cells, the specific conjugates were very effective, much better than daunomycin-dextran and definitely better than when administered i.p.…”

Section: Resultsmentioning

confidence: 95%

Chemotherapy by intravenous administration of conjugates of daunomycin with monoclonal and conventional anti-rat alpha-fetoprotein antibodies.

Tsutsumi¹,

Hurwitz²,

Kashi³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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Monoclonal antibodies to rat a-fetoprotein (AFP) were produced by hybridization of mouse myeloma cells with spleen cells from mice immunized with rat AFP. The monoclonal antibodies as well as horse anti-rat AFP were coupled via a dextran bridge to daunomycin. Both types of conjugates were tested in vitro and in vivo for their anti-tumor activity. They were equally cytotoxic to rat AH66 hepatoma cell line in culture. Rats challenged with hepatoma cells were treated with the conjugates either by intraperitoneal or intravenous injections. Daunomycin conjugates with horse anti-AFP and monoclonal mouse anti-AFP were capable of delaying the tumor development more efficiently than the controls of antibodies or free drug, mixtures of drug with antibodies, and a conjugate ofdrug and normal immunoglobulin. The specific conjugates were considerably more effective when the treatments were given intravenously. The specific conjugates produced 60% long-term survival, whereas the controls delayed only slightly tumor development. Chemotherapeutic studies were performed with both types of conjugates in the treatment of rat hepatoma. Although previously the tumor and the treatments were delivered by the same route, intraperitoneally (i.p.) (1), treatments now also were given intravenously (i.v.). The systemic treatment with the specific carriers ofthe i.p. tumor produced 60% long-term survival, suggesting high efficacy and successful targeting at the tumor sites. MATERIALS AND METHODSSpecific Antibodies to AFP. The preparation ofhorse anti-rat AFP and the purification of the specific antibody by affinity chromatography have been described (10, 11). Monoclonal antirat AFP was prepared by hybridization (2) according to a procedure described by Eshhar et al. (12). Spleen cells were taken from mice that were immunized with rat AFP according to the following schedule. The mice were injected into the footpad twice (10 days apart) with 10 ,Ag of rat hepatomal AFP (13) in complete Freund adjuvant. Six and 5 days prior to the hybridization they received 10 ,g ofAFP, iLv., and i.p., respectively. Positive cultures were detected by solid-phase indirect radioimmunoassay (14), by using as a second antibody "2I-labeled goat anti-mouse F(ab')2 (specific activity, 2 X 10 cpm/mg). They were cloned subsequently in agar or by limiting dilutions. The clones were grown in vitro in culture or in CD2 mice.Tumor Cells. The rat ascites cell line AH66 was used throughout the experiments. It was maintained by i.p. passage in syngeneic Donryu rats or cultivation in vitro (15,16 The publication costs ofthis article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact.

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Section: Resultsmentioning

confidence: 95%

Chemotherapy by intravenous administration of conjugates of daunomycin with monoclonal and conventional anti-rat alpha-fetoprotein antibodies.

Tsutsumi¹,

Hurwitz²,

Kashi³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition in the polymer-bound state the nucleoside antimetabolites might be useful in tumor therapy, since tumor cells show an enhanced pinocytic activity (phagocytosis) compared to normal cells [33,34].…”

Section: Discussionmentioning

confidence: 99%

Dextran-Linked Purine Nucleosides as Substrates and Inhibitors of Adenosine Deaminase

1982

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Dextran-bound adenosine, inosine, and nebularine have been prepared by carbodiimide coupling of their 2',3'-O-(4-carboxyethyl-l-methylbutylidene) cyclic acetal derivatives to 6-aminohexyldextran or 12-aminododecanyldextran. The latter polymers were prepared by cyanogen-bromide activation of dextran T80 followed by reaction with 1,6-diaminohexane or 1 ,12-diaminododecane. A high CNBr concentration leads to high-molecular-weight material, probably due to cross-linking, accompanied by a decrease in the digestion velocity using endo-dextranase from Penicillium species (EC 3.2.1.1 1).The dextran-bound nucleosides, as well as the nucleoside 2', 3'-O-(4-ethoxycarbonyI-l -methylbutylidene) acetal derivatives, were tested as substrates and inhibitors for adenosine deaminase. The K, of the adenosine acetal ester is identical to that of adenosine which shows that acetalation does not hinder complex formation. Since the maximum velocity of deamination is decreased fourfold, the modified substrate does not fit as well as the nucleoside. The polymer-bound acetals show a 3 -8-fold increase of K, or Ki and unchanged V compared to the corresponding acetals while dextranase digestion of the support does not alter the kinetic data. This indicates that the length of the polysaccharide chain does not interfere either with the complex formation or with the catalytic activity of the modified substrate. Since the activation energies of the deamination reactions of adenosine, its acetal ester, and dextran-linked adenosine are all similar (29.8 -32.3 kJ mol-') it is concluded that no diffusion control of the enzymatic reaction results from the binding of the nucleoside acetals to dextran T80.Heterogeneous enzyme-catalysed reactions can be divided into two categories: (a) reactions between soluble substrates and enzymes embedded in biological membranes or other native complex structures ; (b) reactions between a soluble enzyme and a polymer-bound or insoluble substrate [l -61.This prompted us to immobilise substrates and inhibitors of adenosine deaminase via cyclic acetal derivatives onto soluble dextran T80. Dextrans are a group of structurally related polysaccharides (mr, lo5 -10') elaborated by various microorganisms, especially by strains of Leuconostoc. All dextrans contain linear chains of 1 .+ 6-linked a-D-glucopyranose residues as the dominant structural feature [7]. Since we have already immobilised adenosine deaminase on dextran T80 [8], we now have a complete kinetic model system in which either the enzyme or its binding partners are covalently bound to a polymer matrix.The polymer attachment of nucleosides and nucleoside antimetabolites has several implications. (a) From the pharmacological point of view, the brief plasma persistance of small substrates and inhibitors can be overcome by linking the biomolecule to a polymer such as dextran T80, which is used as a blood volume expander. High activity of the modified substrate can only be expected if the position of attachment is carefully chosen and, if possible, a stereochemica...

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“…The reaction proceeds via Schiff base formation, followed by reductive amination by using sodium cyanoborohydride to create stable secondary amine linkages. 27 X-ray photoelectron spectroscopy surveys of surfaces conjugated with streptavidin or neutravidin indicated the presence of 8.0 at.% nitrogen at 398 eV. Analysis by XPS shows that there is ¾12 at.% N (spectra not shown here) in pure streptavidin and neutravidin, therefore we can estimate that the coating of streptavidin or neutravidin on the polystyrene surface is ¾67%.…”

Section: Neutravidin Conjugationmentioning

confidence: 63%

Surface modification of polystyrene biochip for biotin‐labelled protein/streptavidin or neutravidin coupling used in fluorescence assay

Gao

Mathieu

Schawaller³

2004

Surface & Interface Analysis

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A polystyrene biosensing chip to be used as a medical diagnostic tool has been developed. Its surface functionalization is optimized to bind the bioanalytes with high efficiency. Coatings of allyldextran monolayers were carried out on polystyrene chips activated with g-irradiation. The effect of the concentration of allyldextran solution on the coating efficiency was studied by surface-sensitive x-ray photoelectron spectroscopy (XPS) and contact-angle measurements. In a second step, sodium periodate chemistry was applied to functionalize the dextran layer, followed by coupling with streptavidin or neutravidin.

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Higher Antitumor Efficacy of Daunomycin When Linked to Dextran: In Vivo and In Vitro Studies 2

Cited by 118 publications

References 0 publications

Chemotherapy by intravenous administration of conjugates of daunomycin with monoclonal and conventional anti-rat alpha-fetoprotein antibodies.

Chemotherapy by intravenous administration of conjugates of daunomycin with monoclonal and conventional anti-rat alpha-fetoprotein antibodies.

Dextran-Linked Purine Nucleosides as Substrates and Inhibitors of Adenosine Deaminase

Surface modification of polystyrene biochip for biotin‐labelled protein/streptavidin or neutravidin coupling used in fluorescence assay

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