Dataset Information

Pharmacokinetic Evaluation of [11C]CEP-32496 in Nude Mice Bearing BRAFV600E Mutation-Induced Melanomas.

ABSTRACT: CEP-32496, also known as RXDX-105 or Agerafenib, is a new orally active inhibitor for the mutated v-raf murine sarcoma viral oncogene homolog B1 (BRAFV600E), which has attracted considerable attention in clinical trials for the treatment of human cancers. Here, we used carbon-11-labeled CEP-32496 ([11C]CEP-32496) as a positron emission tomography (PET) radiotracer to evaluate its pharmacokinetic properties and explore its potential for in vivo imaging. Following radiotracer synthesis, we performed in vitro binding assays and autoradiography of [11C]CEP-32496 in the A375 melanoma cell line and on tumor tissue sections from mice harboring the BRAFV600E mutation. These were followed by PET scans and biodistribution studies on nude mice bearing subcutaneous A375 cell-induced melanoma. [11C]CEP-32496 showed high binding affinity for BRAFV600E-positive A375 melanoma cells and densely accumulated in the respective tissue sections; this could be blocked by the BRAFV600E selective antagonist sorafenib and by unlabeled CEP-32496. The PET and biodistribution results revealed that [11C]CEP-32496 accumulated continuously but slowly into the tumor within a period of 0 to 60 minutes postinjection in A375-melanoma-bearing nude mice. Metabolite analysis showed high in vivo stability of [11C]CEP-32496 in plasma. Our results indicate that [11C]CEP-32496 has excellent specificity and affinity for the BRAFV600E mutation in vitro, while its noninvasive personalized diagnostic role needs to be studied further.

SUBMITTER: Jiang C

PROVIDER: S-EPMC6156206 | biostudies-literature | 2018 Jan-Dec

REPOSITORIES: biostudies-literature

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Pharmacokinetic Evaluation of [11C]CEP-32496 in Nude Mice Bearing BRAFV600E Mutation-Induced Melanomas.

Jiang Cuiping C Xie Lin L Zhang Yiding Y Fujinaga Masayuki M Mori Wakana W Kurihara Yusuke Y Yamasaki Tomoteru T Wang Feng F Zhang Ming-Rong MR

Molecular imaging 20180101

CEP-32496, also known as RXDX-105 or Agerafenib, is a new orally active inhibitor for the mutated v-raf murine sarcoma viral oncogene homolog B1 (BRAFV600E), which has attracted considerable attention in clinical trials for the treatment of human cancers. Here, we used carbon-11-labeled CEP-32496 ([11C]CEP-32496) as a positron emission tomography (PET) radiotracer to evaluate its pharmacokinetic properties and explore its potential for in vivo imaging. Following radiotracer ...[more]

PMID: 30251592

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Project description:PurposeLarge-scale studies have revealed that appropriate antiangiogenic treatment enables the recovery of the normal structure and function of solid tumor vessels. Epigallocatechin-3-gallate (EGCG), a natural extract of green tea, has multiple effects on angiogenesis. However, normalization of blood vessels due to natural ingredients has not yet been reported. Therefore, we examined the microvasculature, microenvironment, and efficacy of EGCG combined with chemotherapy in a xenograft model.MethodsWe treated A549 cell (human lung adenocarcinoma cell line) xenograft-bearing nude mice with EGCG in vivo. CD31, αSMA, and collagen IV were labeled and detected using quantum-dot double-labeled immunofluorescence to measure microvessel density, microvessel pericyte-coverage index, and collagen IV expression. Vessel-perfusion function was determined by lectin injection, permeability by Evans blue extravasation, interstitial fluid pressure using the wick-in-needle technique, and hypoxia levels using a polarographic electrode and immunohistochemical pimonidazole labeling. Cisplatin concentration in tumor tissue was detected using graphite-furnace atomic absorption spectrophotometry. Xenograft mice were randomized into five groups: treated with saline, cisplatin, EGCG, EGCG + cisplatin on day 1, or EGCG + cisplatin during the vascular normalization window. Tumor-growth delay and tumor-suppression rate were measured to evaluate tumor growth.ResultsEGCG treatment in vivo caused temporary changes, including transient depression of microvessel density, microvessel pericyte-coverage index, and collagen IV expression, transient elevation of vessel perfusion and permeability, and decreased interstitial fluid pressure and hypoxia. During vascular normalization, pretreatment with EGCG increased cisplatin concentration in tumor tissue compared with treatment with cisplatin only. Tumor-growth delay after treatment in the five groups during the vascular normalization window was 6.3±1.51, 7.5±1.57, 8.3±1.79, 12.1±1.35, and 15.4±1.99 days, indicating synergistic EGCG-cisplatin effects, especially during the vascular normalization window (P<0.01).ConclusionEGCG-induced vascular normalization in human lung adenocarcinoma may be a novel modality for enhancing chemotherapy effects.

Project description:Introduction: Kangai (KA) injection, a Chinese herbal injection, is often used in combination with irinotecan (CPT-11) to enhance the effectiveness of anti-colorectal cancer treatment and alleviate side effects. However, the combined administration of this herb-drug pair remains controversial due to limited pre-clinical evidence and safety concerns. This study aimed to determine the pre-clinical herb-drug interactions between CPT-11 and KA injection to provide a reference for their clinical co-administration. Methods: In the pharmacological study, BALB/c mice with CT26 colorectal tumors were divided into four groups and treated with vehicle alone (0.9% saline), CPT-11 injection (100 mg/kg), KA injection (10 mL/kg), or a combination of CPT-11 and KA injection, respectively. The tumor volume of mice was monitored daily to evaluate the therapeutic effect. Daily body weight, survival rate, hematopoietic toxicity, immune organ indices, and gut toxicity were analyzed to study the adverse effects. Healthy Sprague-Dawley rats in the pharmacokinetic study were administered KA injection only (4 mL/kg), or a combination of CPT-11 injection (20 mg/kg) and KA injection, respectively. Six key components of KA injection (oxymatrine, matrine, ginsenoside Rb1, Rg1, Re, and astragaloside IV) in rat plasma samples collected within 24 h after administration were determined by LC-MS/MS. Results: The pharmacological study indicated that KA injection has the potential to enhance the anti-colorectal cancer efficacy of CPT-11 injection and alleviate the severe weight loss induced by CPT-11 injection in tumor-bearing mice. The pharmacokinetic study revealed that co-administration resulted in inhibition of oxymatrine metabolism in rats, evidenced by the significantly reduced Cmax and AUC0-t of its metabolite, matrine (p < 0.05), from 2.23 ± 0.24 to 1.38 ± 0.12 μg/mL and 8.29 ± 1.34 to 5.30 ± 0.79 μg h/mL, respectively. However, due to the similar efficacy of oxymatrine and matrine, this may not compromise the anti-cancer effect of this herb-drug pair. Discussion: This study clarified the pre-clinical pharmacology and pharmacokinetic benefits and risks of the CPT-11-KA combination and provided a reference for their clinical co-administration.

Dataset Information

Pharmacokinetic Evaluation of [11C]CEP-32496 in Nude Mice Bearing BRAFV600E Mutation-Induced Melanomas.

Publications

Pharmacokinetic Evaluation of [<sup>11</sup>C]CEP-32496 in Nude Mice Bearing BRAF<sup>V600E</sup> Mutation-Induced Melanomas.

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