Pharmacokinetics (PK) of the angiogenesis inhibitor ABT-510 in healthy subjects

Karyekar, Chetan S.; Carr, Robert; Andre, A.; Wang, Q.; Facey, I.; Marsh, Kennan; Daszkowski, D.; Humerickhouse, Rod

doi:10.1200/jco.2004.22.90140.3080

Cited by 2 publications

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“…Additionally, ABT-510 was reported to block progression or cause regression of tumor growth in pet dogs. , ABT-526 and ABT-510 are the first in the class of potent inhibitors of angiogenesis that mimic the antiangiogenic function of TSP-1 while avoiding the potentially deleterious side effects associated with the other functional domains of this glycoprotein. ABT-510 is currently in phase II clinical studies. , …”

Section: Discussionmentioning

confidence: 99%

Thrombospondin-1 Mimetic Peptide Inhibitors of Angiogenesis and Tumor Growth: Design, Synthesis, and Optimization of Pharmacokinetics and Biological Activities

et al. 2005

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The heptapeptide 1, NAc-Gly-Val-DIle-Thr-Arg-Ile-ArgNHEt, a structurally modified fragment derived from the second type-1 repeat of thrombospondin-1 (TSP-1), is known to possess antiangiogenic activity. However, therapeutic utility could not be demonstrated because this peptide has a very short half-life in rodents. To optimize the PD/PK profile of 1, we initiated a systematic SAR study. The initial structural modifications were performed at positions 5 and 7 of peptide 1 and at the N- and C-termini. Out of several hundred peptides synthesized, the nonapeptide 5 (ABT-526) emerged as a promising lead. ABT-526 inhibited VEGF-induced HMVEC cell migration and tube formation in the nanomolar range and increased apoptosis of HUAEC cells. ABT-526 showed acceptable PK in rodents, dog, and monkey. ABT-526, when incorporated in an angiogenic pellet implanted in the rat cornea at 10 microM, reduced neovascularization by 92%. Substitution of DalloIle in place of DIle in ABT-526 provided nonapeptide 6 (ABT-510), which was 30-fold less active than ABT-526 in the EC migration but 20-fold more active in the tube formation assay. In comparison to ABT-526, ABT-510 has increased water solubility and slower clearance in dog and monkey. Radiolabeled ABT-510 demonstrated saturable binding to HMVEC cells at 0.02-20 nM concentrations and was displaceable by TSP-1. ABT-510 and ABT-526 were shown to significantly increase apoptosis of HUAEC cells. ABT-510 was effective in blocking neovascularization in the mouse Matrigel plug model and inhibited tumor growth in the mouse Lewis lung carcinoma model. Previous studies had shown that ABT-510 was effective in inhibiting the outgrowth of murine melanoma metastases in syngeneic mice and in blocking the growth of human bladder carcinoma implanted in nude mice. It had been also shown that ABT-510 could regress tumor lesions in pet dogs or cause unexpected stabilization of the disease in advanced canine cancer. ABT-526 and ABT-510 are the first compounds in the class of potent inhibitors of angiogenesis that mimic the antiangiogenic function of TSP-1. ABT-510 is currently in phase II clinical studies.

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Section: Discussionmentioning

confidence: 99%

Thrombospondin-1 Mimetic Peptide Inhibitors of Angiogenesis and Tumor Growth: Design, Synthesis, and Optimization of Pharmacokinetics and Biological Activities

et al. 2005

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“…48 The newer molecular agents such as the TSP analogue (ABT-510) and TSP-1 mimetics (D-isoleucyl enantiomer TSP-1 heptapeptide) are in Phase II clinical trials, which have been shown to reduce micro-vessel density and increase apoptosis in bladder tumours. 49,50 The genes, proteins, and molecules with the potential to alter the muscle invasive UCs with their therapeutic targets are shown in Table 1.…”

Section: Angiogenic-antiangiogenic Factors Vascular Endothelial Growt...mentioning

confidence: 99%

A Short Overview on Therapeutic Biomarkers for Muscle Invasive Bladder Carcinoma

Sadaf,

Ismail

2023

EMJ Urol

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Urothelial carcinoma (UC) is the second most common urologic malignancy after prostatic adenocarcinoma. UC comprises more than 90% of urinary bladder tumours. The intense research involving the different molecular aspects of bladder malignancies offers potential opportunities to improve understanding of bladder cancer biology; helps to identify disease earlier; and improves prediction of outcomes or helps targeted therapy. This review highlights the general concepts of the molecular features: molecular pathways for bladder carcinomas and molecular biomarkers for potential target for treatment of UC of the bladder. This discussion could improve the understating of pathogenesis as well as will provide new therapeutic modules, e.g., targeted therapy. This article is a review of bladder cancer genetics, focusing on molecular changes and their significance in the pathogenesis and progression of muscle invasive UC. Also, the relevant genetic biomarkers and their products, and new therapeutic targets and agents that are being developed are presented here.

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Pharmacokinetics (PK) of the angiogenesis inhibitor ABT-510 in healthy subjects

Cited by 2 publications

References 0 publications

Thrombospondin-1 Mimetic Peptide Inhibitors of Angiogenesis and Tumor Growth: Design, Synthesis, and Optimization of Pharmacokinetics and Biological Activities

Thrombospondin-1 Mimetic Peptide Inhibitors of Angiogenesis and Tumor Growth: Design, Synthesis, and Optimization of Pharmacokinetics and Biological Activities

A Short Overview on Therapeutic Biomarkers for Muscle Invasive Bladder Carcinoma

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