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Enhancing the thera...
Enhancing the therapeutic effects of in vitro targeted radionuclide therapy of 3D multicellular tumor spheroids using the novel stapled MDM2/X-p53 antagonist PM2
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- Mortensen, Anja (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap
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- Morin, Eric (författare)
- Uppsala universitet,Vaskulärbiologi
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- Brown, Christopher J. (författare)
- ASTAR, P53Lab, 8A Biomed Grove,06-04-05 Neuros Immunos, Singapore 138648, Singapore.
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- Lane, David P. (författare)
- ASTAR, P53Lab, 8A Biomed Grove,06-04-05 Neuros Immunos, Singapore 138648, Singapore.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Sci Life Lab, Stockholm, Sweden.
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- Nestor, Marika, 1976- (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap
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(creator_code:org_t)
- 2020-04-16
- 2020
- Engelska.
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Ingår i: EJNMMI Research. - : SPRINGER. - 2191-219X. ; 10
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://ejnmmires.sp...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- Background: Precision therapeutics continuously make advances in cancer therapy, and a field of growing interest is the combination of targeted radionuclide therapy (TRNT) with potential radiosensitizing agents. This study evaluated whether the effects of in vitro TRNT, using the Lu-177-labeled anti-CD44v6 antibody AbN44v6, were potentiated by the novel stapled MDM2/X-p53 antagonist PM2.Materials and methods: Two wt p53 cell lines, HCT116 (colorectal carcinoma) and UM-SCC-74B (head and neck squamous cell carcinoma), expressing different levels of the target antigen, CD44v6, were used. Antigen-specific binding of Lu-177-AbN44v6 was initially verified in a 2D cell assay, after which the potential effects of unlabeled AbN44v6 on downstream phosphorylation of Erk1/2 were evaluated by western blotting. Further, the therapeutic effects of unlabeled AbN44v6, Lu-177-AbN44v6, PM2, or a combination (labeled/unlabeled AbN44v6 +/- PM2) were assessed in 3D multicellular tumor spheroid assays.Results: Radiolabeled antibody bound specifically to CD44v6 on both cell lines. Unlabeled AbN44v6 binding did not induce downstream phosphorylation of Erk1/2 at any of the concentrations tested, and repeated treatments with the unlabeled antibody did not result in any spheroid growth inhibition. Lu-177-AbN44v6 impaired spheroid growth in a dose-dependent and antigen-dependent manner. A single modality treatment with 20 mu M of PM2 significantly impaired spheroid growth in both spheroid models. Furthermore, the combination of TRNT and PM2-based therapy proved significantly more potent than either monotherapy. In HCT116 spheroids, this resulted in a two- and threefold spheroid growth rate decrease for the combination of PM2 and 100 kBq Lu-177-AbN44v6 compared to monotherapies 14-day post treatment. In UM-SCC-74B spheroids, the combination therapy resulted in a reduction in spheroid size compared to the initial spheroid size 10-day post treatment.Conclusion: TRNT using Lu-177-AbN44v6 proved efficient in stalling spheroid growth in a dose-dependent and antigen-dependent manner, and PM2 treatment demonstrated a growth inhibitory effect as a monotherapy. Moreover, by combining TRNT with PM2-based therapy, therapeutic effects of TRNT were potentiated in a 3D multicellular tumor spheroid model. This proof-of-concept study exemplifies the strength and possibility of combining TRNT targeting CD44v6 with PM2-based therapy.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- PM2
- TRNT
- Radiosensitization
- pErk1
- 2 induction
- 3D tumor models
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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