Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pharmacokinetics of tasidotin (ILX651), a depsipeptide currently in phase II for the treatment of advanced solid tumors, and tasidotin-C-carboxylate, the main metabolite, were characterized in male nude mice implanted with LOX tumors, which are sensitive to tasidotin, or H460 tumors, which are resistant to tasidotin. The pharmacokinetics of tasidotin and its metabolites were characterized after single-dose administration of tasidotin (20 and 120 mg/kg), tasidotin-C-carboxylate (150 mg/kg), or tasidotin (53 mg/kg) in the presence and absence of Z-prolyl prolinal (5 mg/kg administered 1 hour prior to tasidotin administration), a competitive antagonist of prolyl oligopeptidase, the enzyme responsible for the metabolism of tasidotin to tasidotin-C-carboxylate. A secondary study was done comparing tumor growth in tasidotin-treated mice with implanted LOX tumors in the presence and absence of Z-prolyl-prolinal. After tasidotin administration, the pharmacokinetics of tasidotin and tasidotin-C-carboxylate were similar in plasma and tumors in LOX- and H460-implanted mice, indicating the resistance was not due to pharmacokinetic factors. Tumor carboxylate concentrations were much higher than in plasma after tasidotin administration. The metabolite appeared to contribute approximately 17% to 33% to the total exposure in LOX tumors and 20% to 49% in H460 tumors but <5% in plasma. Less than 5% of the administered tasidotin dose was converted to tasidotin-C-carboxylate, with no apparent differences between LOX- and H460-treated animals. The presence of Z-prolyl-prolinal decreased the amount of tasidotin converted to tasidotin-C-carboxylate from 5.5% to 0.90%, a reduction of almost 80%. After tasidotin-C-carboxylate administration, the half-life was on the order of minutes compared with hours when observed after tasidotin administration. Tasidotin-C-carboxylate elimination was not dependent on tasidotin pharmacokinetics, suggesting that the rate of efflux from cells into plasma was the rate-limiting step in its elimination. Tasidotin-C-carboxylate was also further metabolized to desprolyl-tasidotin-C-carboxylate, although the metabolite ratios were <10%. Pretreatment with Z-prolyl-prolinal completely abolished the antitumor activity of tasidotin, indicating that the metabolite is the main moiety responsible for activity and that, despite tasidotin itself having activity in vitro, tasidotin is acting mainly as a prodrug.
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PMID:Pharmacokinetics in mice implanted with xenografted tumors after intravenous administration of tasidotin (ILX651) or its carboxylate metabolite. 1817 Sep 85

Fibroblast activation protein (FAP) is a serine protease that is generally accepted to play an important role in tumor growth and other diseases involving tissue remodeling. Currently there are no FAP inhibitors with reported selectivity toward both the closely related dipeptidyl peptidases (DPPs) and prolyl oligopeptidase (PREP). We present the discovery of a new class of FAP inhibitors with a N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold. We have explored the effects of substituting the quinoline ring and varying the position of its sp(2) hybridized nitrogen atom. The most promising inhibitors combined low nanomolar FAP inhibition and high selectivity indices (>10(3)) with respect to both the DPPs and PREP. Preliminary experiments on a representative inhibitor demonstrate that plasma stability, kinetic solubility, and log D of this class of compounds can be expected to be satisfactory.
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PMID:Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold. 2490 Jun 96

Tumor microenvironments (TMEs) are composed of cancer cells, fibroblasts, extracellular matrix, microvessels, and endothelial cells. Two prolyl endopeptidases, fibroblast activation protein (FAP) and prolyl oligopeptidase (POP), are commonly overexpressed by epithelial-derived malignancies, with the specificity of FAP expression by cancer stromal fibroblasts suggesting FAP as a possible therapeutic target. Despite overexpression in most cancers and having a role in angiogenesis, inhibition of POP activity has received little attention as an approach to quench tumor growth. We developed two specific and highly effective pseudopeptide inhibitors, M83, which inhibits FAP and POP proteinase activities, and J94, which inhibits only POP. Both suppressed human colon cancer xenograft growth >90% in mice. By immunohistochemical stains, M83- and J94-treated tumors had fewer microvessels, and apoptotic areas were apparent in both. In response to M83, but not J94, disordered collagen accumulations were observed. Neither M83- nor J94-treated mice manifested changes in behavior, weight, or gastrointestinal function. Tumor growth suppression was more extensive than noted with recently reported efforts by others to inhibit FAP proteinase function or reduce FAP expression. Diminished angiogenesis and the accompanying profound reduction in tumor growth suggest that inhibition of either FAP or POP may offer new therapeutic approaches that directly target TMEs.
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PMID:Suppression of tumor growth in mice by rationally designed pseudopeptide inhibitors of fibroblast activation protein and prolyl oligopeptidase. 2562 98

Prolyl endopeptidase (PREP), also known as prolyl oligopeptidase (POP), is an enzyme that cleaves short peptides (<30 amino acids in length) on the C-terminal side of proline. PREP is highly expressed in multiple carcinomas and is a potential target for cancer therapy. A potent inhibitor of PREP, Y-29794, causes long-lasting inhibition of PREP in mouse tissues. However, there are no reports on Y-29794 effects on cancer cell and tumor proliferation. Using cell line models of aggressive triple-negative breast cancer (TNBC), we show here that Y-29794 inhibited proliferation and induced death in multiple TNBC cell lines. Cell death induced by Y-29794 coincided with inhibition of the IRS1-AKT-mTORC1 survival signaling pathway, although stable depletion of PREP alone was not sufficient to reduce IRS1-AKT-mTORC1 signaling or induce death. These results suggest that Y-29794 elicits its cancer cell killing effect by targeting other mechanisms in addition to PREP. Importantly, Y-29794 inhibited tumor growth when tested in xenograft models of TNBC in mice. Induction of cell death in culture and inhibition of xenograft tumor growth support the potential utility of Y-29794 or its derivatives as a treatment option for TNBC tumors.
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PMID:Prolyl endopeptidase inhibitor Y-29794 blocks the IRS1-AKT-mTORC1 pathway and inhibits survival and in vivo tumor growth of triple-negative breast cancer. 3304 14