Dynamic control of tumor vasculature improves antitumor responses in a regional model of melanoma.
Animals
Blood Circulation
/ drug effects
Cell Line, Tumor
Drug Synergism
Feasibility Studies
Female
Intravital Microscopy
Melanoma, Experimental
/ blood supply
Melphalan
/ administration & dosage
Mice
Mice, Inbred C57BL
Phenylephrine
/ administration & dosage
Saline Solution
/ administration & dosage
Survival Analysis
Treatment Outcome
Xenograft Model Antitumor Assays
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
06 08 2020
06 08 2020
Historique:
received:
23
04
2020
accepted:
24
07
2020
entrez:
9
8
2020
pubmed:
9
8
2020
medline:
16
12
2020
Statut:
epublish
Résumé
Despite advances in therapy for melanoma, heterogeneous responses with limited durability represent a major gap in treatment outcomes. The purpose of this study was to determine whether alteration in tumor blood flow could augment drug delivery and improve antitumor responses in a regional model of melanoma. This approach to altering tumor blood flow was termed "dynamic control." Dynamic control of tumor vessels in C57BL/6 mice bearing B16 melanoma was performed using volume expansion (saline bolus) followed by phenylephrine. Intravital microscopy (IVM) was used to observe changes directly in real time. Our approach restored blood flow in non-functional tumor vessels. It also resulted in increased chemotherapy (melphalan) activity, as measured by formation of DNA adducts. The combination of dynamic control and melphalan resulted in superior outcomes compared to melphalan alone (median time to event 40.0 vs 25.0 days, respectively, p = 0.041). Moreover, 25% (3/12) of the mice treated with the combination approach showed complete tumor response. Importantly, dynamic control plus melphalan did not result in increased adverse events. In summary, we showed that dynamic control was feasible, directly observable, and augmented antitumor responses in a regional model of melanoma. Early clinical trials to determine the translational feasibility of dynamic control are ongoing.
Identifiants
pubmed: 32764623
doi: 10.1038/s41598-020-70233-5
pii: 10.1038/s41598-020-70233-5
pmc: PMC7413248
doi:
Substances chimiques
Saline Solution
0
Phenylephrine
1WS297W6MV
Melphalan
Q41OR9510P
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
13245Subventions
Organisme : NCATS NIH HHS
ID : KL2 TR002379
Pays : United States
Organisme : NIH HHS
ID : S10OD016450
Pays : United States
Organisme : NCI NIH HHS
ID : P30CA016056
Pays : United States
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