Neural progenitor cell-mediated delivery of interferon beta improves neuroblastoma response to cyclophosphamide

Thomas L. Sims, John B. Hamner, Rebecca A. Bush, Regan Williams, Junfang Zhou, Seung U. Kim, Karen S. Aboody, Mary K. Danks, Andrew M. Davidoff

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: We have shown that continuous systemic delivery of interferon beta (IFN-β) remodels dysfunctional tumor vasculature, thereby improving tumor perfusion and enhancing delivery and efficacy of chemotherapeutic drugs. We hypothesized that because of their inherent tumor tropism, neural progenitor cells (NPCs) engineered to express IFN-β could also effect maturation of tumor vasculature without generating high systemic levels of IFN-β. Methods: Mice with luciferase-expressing disseminated human neuroblastoma were divided into four groups of equal tumor burden by bioluminescence imaging: (1) untreated controls; (2) NPC-IFN-β only; (3) cyclophosphamide (CTX) only; and (4) NPC-IFN-β in combination with CTX. Two million NPC-IFN-β cells were administered twice, 7 days apart, starting 21 days after tail vein administration of tumor cells. CTX was administered every 6 days for three doses. Mice were killed at 6 weeks, livers and kidneys weighed, and tumor removed for immunohistochemical staining for endothelial cells (CD34), pericytes (α-SMA), apoptosis (TUNEL [terminal deoxynucleotidyl transferase dUTP nick-end labeling]), and diI-labeled NPCs. Results: Fluorescent-labeled NPCs confirmed localization of these cells to tumors. The α-SMA/CD34 ratio, a marker for vascular maturation, greatly increased in NPC-IFN-β-treated tumors compared with controls. Bioluminescent signal from luciferase-expressing tumor cells, reflecting tumor burden, was lower with combination therapy than control or either monotherapy, and combination therapy resulted in far less tumor burden by weight in the kidneys and liver. Conclusions: Targeted delivery of IFN-β with NPCs produced low circulating levels of IFN-β, yet the maturing effect on the tumor vasculature and the enhanced efficacy of adjuvant therapy was maintained. Thus, combination therapy of NPC-IFN-β with CTX warrants further investigation for the treatment of high-risk neuroblastoma patients.

Original languageEnglish (US)
Pages (from-to)3259-3267
Number of pages9
JournalAnnals of Surgical Oncology
Volume15
Issue number11
DOIs
StatePublished - Nov 1 2008

Fingerprint

Interferon-beta
Neuroblastoma
Cyclophosphamide
Stem Cells
Neoplasms
Tumor Burden
Luciferases
Kidney
Therapeutics
Pericytes
Tropism
DNA Nucleotidylexotransferase
Liver
Blood Vessels
Tail
Veins
Endothelial Cells
Perfusion
Apoptosis
Staining and Labeling

All Science Journal Classification (ASJC) codes

  • Surgery
  • Oncology

Cite this

Neural progenitor cell-mediated delivery of interferon beta improves neuroblastoma response to cyclophosphamide. / Sims, Thomas L.; Hamner, John B.; Bush, Rebecca A.; Williams, Regan; Zhou, Junfang; Kim, Seung U.; Aboody, Karen S.; Danks, Mary K.; Davidoff, Andrew M.

In: Annals of Surgical Oncology, Vol. 15, No. 11, 01.11.2008, p. 3259-3267.

Research output: Contribution to journalArticle

Sims, TL, Hamner, JB, Bush, RA, Williams, R, Zhou, J, Kim, SU, Aboody, KS, Danks, MK & Davidoff, AM 2008, 'Neural progenitor cell-mediated delivery of interferon beta improves neuroblastoma response to cyclophosphamide', Annals of Surgical Oncology, vol. 15, no. 11, pp. 3259-3267. https://doi.org/10.1245/s10434-008-0103-z
Sims, Thomas L. ; Hamner, John B. ; Bush, Rebecca A. ; Williams, Regan ; Zhou, Junfang ; Kim, Seung U. ; Aboody, Karen S. ; Danks, Mary K. ; Davidoff, Andrew M. / Neural progenitor cell-mediated delivery of interferon beta improves neuroblastoma response to cyclophosphamide. In: Annals of Surgical Oncology. 2008 ; Vol. 15, No. 11. pp. 3259-3267.
@article{5c90645c6ad5422ca157a03282f261ae,
title = "Neural progenitor cell-mediated delivery of interferon beta improves neuroblastoma response to cyclophosphamide",
abstract = "Background: We have shown that continuous systemic delivery of interferon beta (IFN-β) remodels dysfunctional tumor vasculature, thereby improving tumor perfusion and enhancing delivery and efficacy of chemotherapeutic drugs. We hypothesized that because of their inherent tumor tropism, neural progenitor cells (NPCs) engineered to express IFN-β could also effect maturation of tumor vasculature without generating high systemic levels of IFN-β. Methods: Mice with luciferase-expressing disseminated human neuroblastoma were divided into four groups of equal tumor burden by bioluminescence imaging: (1) untreated controls; (2) NPC-IFN-β only; (3) cyclophosphamide (CTX) only; and (4) NPC-IFN-β in combination with CTX. Two million NPC-IFN-β cells were administered twice, 7 days apart, starting 21 days after tail vein administration of tumor cells. CTX was administered every 6 days for three doses. Mice were killed at 6 weeks, livers and kidneys weighed, and tumor removed for immunohistochemical staining for endothelial cells (CD34), pericytes (α-SMA), apoptosis (TUNEL [terminal deoxynucleotidyl transferase dUTP nick-end labeling]), and diI-labeled NPCs. Results: Fluorescent-labeled NPCs confirmed localization of these cells to tumors. The α-SMA/CD34 ratio, a marker for vascular maturation, greatly increased in NPC-IFN-β-treated tumors compared with controls. Bioluminescent signal from luciferase-expressing tumor cells, reflecting tumor burden, was lower with combination therapy than control or either monotherapy, and combination therapy resulted in far less tumor burden by weight in the kidneys and liver. Conclusions: Targeted delivery of IFN-β with NPCs produced low circulating levels of IFN-β, yet the maturing effect on the tumor vasculature and the enhanced efficacy of adjuvant therapy was maintained. Thus, combination therapy of NPC-IFN-β with CTX warrants further investigation for the treatment of high-risk neuroblastoma patients.",
author = "Sims, {Thomas L.} and Hamner, {John B.} and Bush, {Rebecca A.} and Regan Williams and Junfang Zhou and Kim, {Seung U.} and Aboody, {Karen S.} and Danks, {Mary K.} and Davidoff, {Andrew M.}",
year = "2008",
month = "11",
day = "1",
doi = "10.1245/s10434-008-0103-z",
language = "English (US)",
volume = "15",
pages = "3259--3267",
journal = "Annals of Surgical Oncology",
issn = "1068-9265",
publisher = "Springer New York",
number = "11",

}

TY - JOUR

T1 - Neural progenitor cell-mediated delivery of interferon beta improves neuroblastoma response to cyclophosphamide

AU - Sims, Thomas L.

AU - Hamner, John B.

AU - Bush, Rebecca A.

AU - Williams, Regan

AU - Zhou, Junfang

AU - Kim, Seung U.

AU - Aboody, Karen S.

AU - Danks, Mary K.

AU - Davidoff, Andrew M.

PY - 2008/11/1

Y1 - 2008/11/1

N2 - Background: We have shown that continuous systemic delivery of interferon beta (IFN-β) remodels dysfunctional tumor vasculature, thereby improving tumor perfusion and enhancing delivery and efficacy of chemotherapeutic drugs. We hypothesized that because of their inherent tumor tropism, neural progenitor cells (NPCs) engineered to express IFN-β could also effect maturation of tumor vasculature without generating high systemic levels of IFN-β. Methods: Mice with luciferase-expressing disseminated human neuroblastoma were divided into four groups of equal tumor burden by bioluminescence imaging: (1) untreated controls; (2) NPC-IFN-β only; (3) cyclophosphamide (CTX) only; and (4) NPC-IFN-β in combination with CTX. Two million NPC-IFN-β cells were administered twice, 7 days apart, starting 21 days after tail vein administration of tumor cells. CTX was administered every 6 days for three doses. Mice were killed at 6 weeks, livers and kidneys weighed, and tumor removed for immunohistochemical staining for endothelial cells (CD34), pericytes (α-SMA), apoptosis (TUNEL [terminal deoxynucleotidyl transferase dUTP nick-end labeling]), and diI-labeled NPCs. Results: Fluorescent-labeled NPCs confirmed localization of these cells to tumors. The α-SMA/CD34 ratio, a marker for vascular maturation, greatly increased in NPC-IFN-β-treated tumors compared with controls. Bioluminescent signal from luciferase-expressing tumor cells, reflecting tumor burden, was lower with combination therapy than control or either monotherapy, and combination therapy resulted in far less tumor burden by weight in the kidneys and liver. Conclusions: Targeted delivery of IFN-β with NPCs produced low circulating levels of IFN-β, yet the maturing effect on the tumor vasculature and the enhanced efficacy of adjuvant therapy was maintained. Thus, combination therapy of NPC-IFN-β with CTX warrants further investigation for the treatment of high-risk neuroblastoma patients.

AB - Background: We have shown that continuous systemic delivery of interferon beta (IFN-β) remodels dysfunctional tumor vasculature, thereby improving tumor perfusion and enhancing delivery and efficacy of chemotherapeutic drugs. We hypothesized that because of their inherent tumor tropism, neural progenitor cells (NPCs) engineered to express IFN-β could also effect maturation of tumor vasculature without generating high systemic levels of IFN-β. Methods: Mice with luciferase-expressing disseminated human neuroblastoma were divided into four groups of equal tumor burden by bioluminescence imaging: (1) untreated controls; (2) NPC-IFN-β only; (3) cyclophosphamide (CTX) only; and (4) NPC-IFN-β in combination with CTX. Two million NPC-IFN-β cells were administered twice, 7 days apart, starting 21 days after tail vein administration of tumor cells. CTX was administered every 6 days for three doses. Mice were killed at 6 weeks, livers and kidneys weighed, and tumor removed for immunohistochemical staining for endothelial cells (CD34), pericytes (α-SMA), apoptosis (TUNEL [terminal deoxynucleotidyl transferase dUTP nick-end labeling]), and diI-labeled NPCs. Results: Fluorescent-labeled NPCs confirmed localization of these cells to tumors. The α-SMA/CD34 ratio, a marker for vascular maturation, greatly increased in NPC-IFN-β-treated tumors compared with controls. Bioluminescent signal from luciferase-expressing tumor cells, reflecting tumor burden, was lower with combination therapy than control or either monotherapy, and combination therapy resulted in far less tumor burden by weight in the kidneys and liver. Conclusions: Targeted delivery of IFN-β with NPCs produced low circulating levels of IFN-β, yet the maturing effect on the tumor vasculature and the enhanced efficacy of adjuvant therapy was maintained. Thus, combination therapy of NPC-IFN-β with CTX warrants further investigation for the treatment of high-risk neuroblastoma patients.

UR - http://www.scopus.com/inward/record.url?scp=55149106765&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=55149106765&partnerID=8YFLogxK

U2 - 10.1245/s10434-008-0103-z

DO - 10.1245/s10434-008-0103-z

M3 - Article

C2 - 18726131

AN - SCOPUS:55149106765

VL - 15

SP - 3259

EP - 3267

JO - Annals of Surgical Oncology

JF - Annals of Surgical Oncology

SN - 1068-9265

IS - 11

ER -