| 1. |
- Berta, Judit, et al.
(författare)
-
Apelin promotes blood and lymph vessel formation and the growth of melanoma lung metastasis
- 2021
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Apelin, a ligand of the APJ receptor, is overexpressed in several human cancers and plays an important role in tumor angiogenesis and growth in various experimental systems. We investigated the role of apelin signaling in the malignant behavior of cutaneous melanoma. Murine B16 and human A375 melanoma cell lines were stably transfected with apelin encoding or control vectors. Apelin overexpression significantly increased melanoma cell migration and invasion in vitro, but it had no impact on its proliferation. In our in vivo experiments, apelin significantly increased the number and size of lung metastases of murine melanoma cells. Melanoma cell proliferation rates and lymph and blood microvessel densities were significantly higher in the apelin-overexpressing pulmonary metastases. APJ inhibition by the competitive APJ antagonist MM54 significantly attenuated the in vivo pro-tumorigenic effects of apelin. Additionally, we detected significantly elevated circulating apelin and VEGF levels in patients with melanoma compared to healthy controls. Our results show that apelin promotes blood and lymphatic vascularization and the growth of pulmonary metastases of skin melanoma. Further studies are warranted to validate apelin signaling as a new potential therapeutic target in this malignancy.
|
|
| 2. |
- James, Connell, et al.
(författare)
-
Localization of Sunitinib in in vivo Animal and in vitro Experimental Models by MALDI Mass Spectrometry Imaging
- 2015
-
Ingår i: Analytical and Bioanalytical Chemistry. - : Springer Science and Business Media LLC. - 1618-2642 .- 1618-2650. ; 407:8, s. 2245-2253
-
Tidskriftsartikel (refereegranskat)abstract
- The spatial distribution of an anti-cancer drug and its intended target within a tumor plays a major role on determining how effective the drug can be at tackling the tumor. This study provides data regarding the lateral distribution of sunitinib, an oral antiangiogenic receptor tyrosine kinase inhibitor using an in vitro animal model as well as an in vitro experimental model that involved deposition of a solution of sunitinib onto tissue sections. All tumor sections were analyzed by matrix-assisted laser desorption/ionization mass spectrometry imaging and compared with subsequent histology staining. Six tumors at four different time points after commencement of in vivo sunitinib treatment were examined to observe the patterns of drug uptake. The levels of sunitinib present in in vivo treated tumor sections increased continuously until day seven but a decrease was observed at day 10. Furthermore, the in vitro experimental model was adjustable to produce a drug level similar to that obtained in the in vivo model experiments. The distribution of sunitinib in tissue sections treated in vitro appeared to agree with the histological structure of tumors suggesting that this approach may be useful for testing drug update.
|
|
| 3. |
- Kwon, Ho Jeong, et al.
(författare)
-
Drug Compound Characterization by Mass Spectrometry Imaging in Cancer Tissue
- 2015
-
Ingår i: Archives of Pharmacal Research. - : Springer Science and Business Media LLC. - 1976-3786 .- 0253-6269. ; 38:9, s. 1718-1727
-
Forskningsöversikt (refereegranskat)abstract
- MALDI Mass spectrometry imaging (MSI) provides a technology platform that allows the accurate visualization of unlabeled small molecules within the two-dimensional spaces of tissue samples. MSI has proven to be a powerful tool-box concept in the development of new drugs. MSI allows unlabeled drug compounds and drug metabolites to be detected and identified and quantified according to their mass-to-charge ratios (m/z) at high resolution in complex tissue environments. Such drug characterization in situ, by both spatial and temporal behaviors within tissue compartments, provide new understandings of the dynamic processes impacting drug uptake and metabolism at the local sites targeted by therapy. Further, MSI in combination with histology and immunohistochemistry, provides the added value of defining the context of cell biology present at the sites of drug localization thus providing invaluable information relating to treatment efficacy. In this report we provide mass spectrometry imaging data within various cancers such as malignant melanoma in patients administered with Vemurafenib, a protein kinase inhibitor that is targeting both the BRAF, and ERK mutated target proteins and that has shown significant efficacy in restraining disease progression. We also provide an overview of other examples of the new generation of targeted drugs, and demonstrate the data on personalized medicine drugs localization within tumor compartments within in vivo models. In these cancer models we provide detailed data on drug and target protein co-localization of YCG185 and Sunitinib. These drugs are targeting VEGFR2 within the angiogenesis mechanism. Our ability to resolve drug uptake at targeted sites of directed therapy provides important opportunities for increasing our understanding about the mode of action of drug activity within the environment of disease.
|
|
| 4. |
- Török, Szilvia, et al.
(författare)
-
Localization of sunitinib, its metabolites and its target receptors in tumor bearing mice: a MALDI mass spectrometry imaging study
- 2015
-
Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 172:4, s. 1148-1163
-
Tidskriftsartikel (refereegranskat)abstract
- A functional blood vessel network is essential for maintaining the necessary oxygen and nutrient levels in solid tumors. Thus, the inhibition of blood vessel growth by different antiangiogenic agents has become one of the most important topics in cancer research over the past few decades. The in vitro studies of these drugs are promising, but both the in vivo and the clinical experiences are controversial. Therefore, investigating the pharmacokinetic parameters of these compounds is a pivotal issue in drug development. In this study, the detection and the adsorption, distribution, metabolism, elimination (ADME) of the antiangiogenic receptor tyrosine kinase inhibitor (RTKI) sunitinib is analyzed in a subcutaneous syngeneic murine tumor model of colorectal cancer. The parent molecule of sunitinib was detected at m/z 399.218 with fragment ions at m/z 326.1 and 283.1 with matrix assisted laser desorption ionization (MALDI) technique. Metabolites of the drug were measured in blood samples and main metabolites were found in tumor, liver and kidney tissues at m/z 371.188, 397.203 and 415.214. Tissue distribution of the drug and its metabolites showed an overlapping pattern by MALDI imaging. The present study supports the role of the MALDI technique in the ADME characterization of drug candidates in preclinical drug development.
|
|
