Triple combination of lomustine, temozolomide and irradiation reduces canine glioma cell survival in vitro

Fuchs, Daniel; Rohrer Bley, Carla; Morandi, Luca; Tonon, Caterina; Weyland, Mathias S.; Nytko, Katarzyna J.

doi:10.1002/vms3.1181

Please use this identifier to cite or link to this item: https://doi.org/10.21256/zhaw-28428

Publication type:	Article in scientific journal
Type of review:	Peer review (publication)
Title:	Triple combination of lomustine, temozolomide and irradiation reduces canine glioma cell survival in vitro
Authors:	Fuchs, Daniel Rohrer Bley, Carla Morandi, Luca Tonon, Caterina Weyland, Mathias S. Nytko, Katarzyna J.
et. al:	No
DOI:	10.1002/vms3.1181 10.21256/zhaw-28428
Published in:	Veterinary Medicine and Science
Volume(Issue):	9
Issue:	4
Page(s):	1573
Pages to:	1583
Issue Date:	Jul-2023
Publisher / Ed. Institution:	Wiley
ISSN:	2053-1095
Language:	English
Subjects:	O-6-methylguanine-DNA methyltransferase (MGMT); Brain tumour; Chemoradiation; Dog; In vitro; Animal; Temozolomide; Lomustine; Dacarbazine; Cell survival; Glioma; Dog disease
Subject (DDC):	590: Animals (Zoology) 615: Pharmacology and therapeutics
Abstract:	Background: Combined chemoradiation offers a promising therapeutic strategy for dogs with glioma. The alkylating agents temozolomide (TMZ) and lomustine (CCNU) penetrate the blood-brain barrier, and doses for dogs are established. Whether such combinations are clinically advantageous remains to be explored together with tumour-specific markers. Objective: To investigate if triple combination of lomustine, temozolomide and irradiation reduces canine glioma cell survival in vitro. Methods: We evaluated the sensitising effect of CCNU alone and in combination with TMZ-irradiation in canine glioma J3T-BG cells and long-term drug-exposed subclones by using clonogenic survival and proliferation assays. Bisulphite-SEQ and Western Blot were used to investigate molecular alterations. Results: TMZ (200 μM) or CCNU alone (5 μM) reduced the irradiated survival fraction (4 Gy) from 60% to 38% (p = 0.0074) and 26% (p = 0.0002), respectively. The double-drug combination reduced the irradiated survival fraction (4 Gy) more potently to 12% (p < 0.0001). After long-term drug exposure, both subclones show higher IC50 values against CCNU and TMZ. For CCNU-resistant cells, both, single-drug CCNU (p = 0.0006) and TMZ (p = 0.0326) treatment combined with irradiation (4 Gy) remained effective. The double-drug-irradiation combination reduced the cell survival by 86% (p < 0.0001), compared to 92% in the parental (nonresistant) cell line. For TMZ-resistant cells, only the double-drug combination with irradiation (4 Gy) reduced the cell survival by 88% (p = 0.0057) while single-drug treatment lost efficacy. Chemoresistant cell lines demonstrated higher P-gp expression while MGMT-methylation profile analysis showed a general high methylation level in the parental and long-term treated cell lines. Conclusions: Our findings indicate that combining CCNU with TMZ-irradiation significantly reduces canine glioma cell survival. Such a combination could overcome current challenges of therapeutic resistance to improve overall patient survival.
URI:	https://digitalcollection.zhaw.ch/handle/11475/28428
Fulltext version:	Published version
License (according to publishing contract):	CC BY-NC-ND 4.0: Attribution - Non commercial - No derivatives 4.0 International
Departement:	School of Engineering
Organisational Unit:	Institute of Applied Mathematics and Physics (IAMP)
Appears in collections:	Publikationen School of Engineering

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Fuchs, D., Rohrer Bley, C., Morandi, L., Tonon, C., Weyland, M. S., & Nytko, K. J. (2023). Triple combination of lomustine, temozolomide and irradiation reduces canine glioma cell survival in vitro. Veterinary Medicine and Science, 9(4), 1573–1583. https://doi.org/10.1002/vms3.1181

Fuchs, D. et al. (2023) ‘Triple combination of lomustine, temozolomide and irradiation reduces canine glioma cell survival in vitro’, Veterinary Medicine and Science, 9(4), pp. 1573–1583. Available at: https://doi.org/10.1002/vms3.1181.

D. Fuchs, C. Rohrer Bley, L. Morandi, C. Tonon, M. S. Weyland, and K. J. Nytko, “Triple combination of lomustine, temozolomide and irradiation reduces canine glioma cell survival in vitro,” Veterinary Medicine and Science, vol. 9, no. 4, pp. 1573–1583, Jul. 2023, doi: 10.1002/vms3.1181.

FUCHS, Daniel, Carla ROHRER BLEY, Luca MORANDI, Caterina TONON, Mathias S. WEYLAND und Katarzyna J. NYTKO, 2023. Triple combination of lomustine, temozolomide and irradiation reduces canine glioma cell survival in vitro. Veterinary Medicine and Science. Juli 2023. Bd. 9, Nr. 4, S. 1573–1583. DOI 10.1002/vms3.1181

Fuchs, Daniel, Carla Rohrer Bley, Luca Morandi, Caterina Tonon, Mathias S. Weyland, and Katarzyna J. Nytko. 2023. “Triple Combination of Lomustine, Temozolomide and Irradiation Reduces Canine Glioma Cell Survival in Vitro.” Veterinary Medicine and Science 9 (4): 1573–83. https://doi.org/10.1002/vms3.1181.

Fuchs, Daniel, et al. “Triple Combination of Lomustine, Temozolomide and Irradiation Reduces Canine Glioma Cell Survival in Vitro.” Veterinary Medicine and Science, vol. 9, no. 4, July 2023, pp. 1573–83, https://doi.org/10.1002/vms3.1181.