A nonantigenic covalent streptokinase-polyethylene glycol complex with plasminogen activator function.

Rajagopalan, Shrin; Gonias, Steven L.; Pizzo, Salvatore V.

doi:10.1172/jci111715

Cited by 80 publications

(37 citation statements)

References 27 publications

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“…The respective half-times were 8 and 63 min. The clearance rate of GRGDS is therefore similar to that of other small protein molecules tested in previous studies (50,51). The rapid clearance of GRGDS suggests that peptide-mediated inhibition of experimental metastasis occurs over the initial postinjection time period, since the concentration of peptide in plasma would be expected to fall to < 100 ,ug/ml within 30 min of injection.…”

Section: Specificity Ofpeptide Inhibition Ofexperimental Metastasissupporting

confidence: 80%

Investigation of the biological effects of anti-cell adhesive synthetic peptides that inhibit experimental metastasis of B16-F10 murine melanoma cells.

Humphries¹,

Yamada²,

Olden³

1988

J. Clin. Invest.

155

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The experimental metastasis of B16-F10 murine melanoma cells is blocked by the anti-cell adhesive pentapeptide GlyArg-Gly-Asp-Ser (GRGDS) derived from the central cellbinding domain of fibronectin. In this report, we show that peptide treatment substantially extends the survival time for mice injected intravenously with B16-F1O cells (8/8 vs. 0/8 mice alive at 150 d), thereby demonstrating the potential efficacy of GRGDS treatment in protection against metastatic colonization. We have also examined the specificity of GRGDS activity by testing a series of related homologues for their effects on experimental metastasis. The overall profile of the relative inhibitory activities of these peptides closely matched their previously established capacity to disrupt adhesion in vitro. Lung retention studies with radiolabeled B16-F1O cells revealed an accelerated rate of cell loss from the lung 0-6 h after coinjection with the active peptide GRGDS. This early effect of GRGDS was consistent with its short circulatory half-life, which was found to be 8 min. Taken together, these results suggest that peptide-mediated inhibition of pulmonary colonization is due to interference with B16-F1O cell adhesion to structures in the target organ. Possible peptide interference in tumor cell-blood cell interactions was examined in order to assess (a) possible biological side-effects of peptide treatment and (b) whether such interactions might be an alternative mechanism for GRGDS-mediated inhibition of pulmonary colonization. GRGDS was found to retain full inhibitory activity when coinjected with B16-F10 cells into mice in which platelet function was impaired by acetylsalicylic acid treatment or into thrombocytopenic mice treated with antiplatelet serum (76-93% inhibition of colony formation). These data suggest that platelet involvement in the effects of the peptide is minimal. Similarly, GRGDS was also found to be a potent inhibitor of experimental metastasis in natural killer (NK) cell-deficient beige mice (86% inhibition), thereby discounting the possibility that GRGDS artifactually enhanced NK cell activity. We conclude as a result of these studies that cell-binding fibronectin peptides are specific inhibitors of experimental metastasis that prolong survival, that they appear to function by blocking the adhesion of B16-F1O cells to structures in the target organ, and that they do not appear to act through side effects on certain metastasis-related blood cell functions. In the future, deriva-

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Section: Specificity Ofpeptide Inhibition Ofexperimental Metastasissupporting

confidence: 80%

Investigation of the biological effects of anti-cell adhesive synthetic peptides that inhibit experimental metastasis of B16-F10 murine melanoma cells.

Humphries¹,

Yamada²,

Olden³

1988

J. Clin. Invest.

155

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“…Similarly, PEGylated streptokinase proteins also maintain good activator function but are protected from proteolytic degradation and display decreased antigenicity due to increased steric interference [107,108]. Currently, the only modified streptokinase approved for human use is acylated plasminogenstreptokinase activator complex (APSAC; antistreplase) [93].…”

Section: Second Generation Thrombolytic Therapeutics Based On Streptomentioning

confidence: 99%

The Role of Streptokinase as a Virulence Determinant of Streptococcus pyogenes – Potential for Therapeutic Targeting

McArthur

Cook²,

Venturini³

et al. 2012

CDT

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. (2012). The role of streptokinase as a virulence determinant of streptococcus pyogenes -potential for therapeutic targeting. Current Drug Targets, 13 (3), 297-307. The role of streptokinase as a virulence determinant of streptococcus pyogenes -potential for therapeutic targeting AbstractStreptococcus pyogenes is a major human pathogen responsible for numerous diseases ranging from uncomplicated skin and throat infections to severe, life threatening invasive disease such as necrotising fasciitis and streptococcal toxic shock syndrome. These severe invasive infections progress rapidly and produce high rates of morbidity and mortality despite the implementation of aggressive treatment plans. The activation of plasminogen and the acquisition of plasmin activity at the bacterial cell surface is critical for the invasive pathogenesis of this organism. To facilitate this process, S. pyogenes secrete streptokinase, a potent plasminogen activating protein. Here, we describe the role of streptokinase in invasive pathogenesis and discuss some potentially useful strategies for disruption of streptokinase mediated plasminogen activation which could be employed to treat severe invasive S. pyogenes infections. AbstractStreptococcus pyogenes is a major human pathogen responsible for numerous diseases ranging from uncomplicated skin and throat infections to severe, life threatening invasive disease such as necrotising fasciitis and streptococcal toxic shock syndrome.These severe invasive infections progress rapidly and produce high rates of morbidity and mortality despite the implementation of aggressive treatment plans. The activation of plasminogen and the acquisition of plasmin activity at the bacterial cell surface is critical for the invasive pathogenesis of this organism. To facilitate this process, S. pyogenes secrete streptokinase, a potent plasminogen activating protein.Here, we describe the role of streptokinase in invasive pathogenesis and discuss some potentially useful strategies that disrupt streptokinase mediated plasminogen activation and could be employed to treat severe invasive S. pyogenes infections.3

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“…Firstly, PEG was modified by a known method [44,45], which is based on the reaction of the hydroxyl groups of the polymer with ethylenediamine in the presence of CDI [46]. However, yields were small (Table 1).…”

Section: Synthesis Of Diamine Pegmentioning

confidence: 99%

PLA-b-PEG/magnetite hyperthermic agent prepared by Ugi four component condensation

Icart¹,

Santos²,

Pereira³

et al. 2016

Express Polym. Lett.

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A nonantigenic covalent streptokinase-polyethylene glycol complex with plasminogen activator function.

Cited by 80 publications

References 27 publications

Investigation of the biological effects of anti-cell adhesive synthetic peptides that inhibit experimental metastasis of B16-F10 murine melanoma cells.

Investigation of the biological effects of anti-cell adhesive synthetic peptides that inhibit experimental metastasis of B16-F10 murine melanoma cells.

The Role of Streptokinase as a Virulence Determinant of Streptococcus pyogenes – Potential for Therapeutic Targeting

PLA-b-PEG/magnetite hyperthermic agent prepared by Ugi four component condensation

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