In vivo effects of chemotherapy on oncogenic pathways in colorectal cancer.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Carcinogenesis
/ drug effects
Cell Proliferation
/ drug effects
Colorectal Neoplasms
/ drug therapy
Female
Fluorouracil
/ pharmacology
Heterografts
/ drug effects
Humans
Leucovorin
/ pharmacology
Male
Mice
Mice, Inbred NOD
Mice, SCID
Oncogenes
/ drug effects
Organoplatinum Compounds
/ pharmacology
Signal Transduction
/ drug effects
MAPK
NOTCH
WNT
chemotherapy
colon and colorectal cancer
Journal
Cancer science
ISSN: 1349-7006
Titre abrégé: Cancer Sci
Pays: England
ID NLM: 101168776
Informations de publication
Date de publication:
Aug 2019
Aug 2019
Historique:
received:
18
03
2019
revised:
06
05
2019
accepted:
20
05
2019
pubmed:
24
5
2019
medline:
14
8
2019
entrez:
24
5
2019
Statut:
ppublish
Résumé
Patients with advanced colorectal cancer often are treated with systemic cytotoxic therapy using fluorouracil (5-FU), oxaliplatin, irinotecan, and FOLFOX or FOLFIRI combination protocols. Additionally, signaling pathways that are active in colorectal cancer can be therapeutically targeted. Herein, we examined whether chemotherapy impacts on WNT, MAPK and NOTCH signaling pathways in xenograft models of colon cancer. Furthermore, we tested whether combining chemotherapy with MAPK and NOTCH inhibition has superior therapeutic effects. We show that colon cancer cells with high WNT, MAPK and NOTCH activity are variably affected but generally persist in xenograft tumors under different chemotherapeutic regimens, indicating limited effects of cytotoxic therapy on oncogenic signaling pathways. Although these results provided a rationale to additionally target pathway activity, we found no significant increase in therapy response when combining MAPK and NOTCH inhibition with fluorouracil chemotherapy. We attribute this finding to a decrease in tumor cell proliferation upon MAPK and NOTCH inhibition, resulting in reduced effectiveness of cytotoxic treatment. Therapeutic benefits of combining chemotherapy with targeting of oncogenic signaling pathways must therefore be critically evaluated for patients with colorectal cancer.
Identifiants
pubmed: 31119819
doi: 10.1111/cas.14077
pmc: PMC6676136
doi:
Substances chimiques
Organoplatinum Compounds
0
Leucovorin
Q573I9DVLP
Fluorouracil
U3P01618RT
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2529-2539Subventions
Organisme : Rudolf Bartling Stiftung
Organisme : Deutsche Krebshilfe
ID : 111669
Informations de copyright
© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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