Increased oxidative stress created by adenoviral MnSOD or CuZnSOD plus BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) inhibits breast cancer cell growth

Christine J. Weydert, Yuping Zhang, Wenqing Sun, Trent A. Waugh, Melissa LT Teoh-Fitzgerald, Kelly K. Andringa, Nukhet Aykin-Burns, Douglas R. Spitz, Brian J. Smith, Larry W. Oberley

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Superoxide dismutases (SODs) have been found to decrease tumor formation and angiogenesis. SOD gene therapy, as with many other gene transfer strategies, may not completely inhibit tumor growth on its own. Thus, concomitant therapies are necessary to completely control the spread of this disease. We hypothesized that intratumoral injection of AdSOD in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) chemotherapy would synergistically inhibit breast cancer growth. Our data indicate that BCNU when combined with SOD overexpression increased oxidative stress as suggested by elevated glutathione disulfide (GSSG) production in one of three breast cancer cell lines tested, at least in part due to glutathione reductase (GR) inactivation. The increased oxidative stress caused by BCNU combined with adenovirally expressed SODs, manganese or copper zinc SOD, decreased growth and survival in the three cell lines tested in vitro, but had the largest effect in the MDA-MB231 cell line, which showed the largest amount of oxidative stress. Delivery of MnSOD and BCNU intratumorally completely inhibited MDA-MB231 xenograft growth and increased nude mouse survival in vivo. Intravenous (iv) BCNU, recapitulating clinical usage, and intratumoral AdMnSOD delivery, to provide tumor specificity, provided similar decreased growth and survival in our nude mouse model. This cancer therapy produced impressive results, suggesting the potential use of oxidative stress-induced growth inhibitory treatments for breast cancer patients.

Original languageEnglish (US)
Pages (from-to)856-867
Number of pages12
JournalFree Radical Biology and Medicine
Volume44
Issue number5
DOIs
StatePublished - Mar 1 2008

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Carmustine
Oxidative stress
Cell growth
Oxidative Stress
Superoxide Dismutase
Breast Neoplasms
Growth
Tumors
Glutathione Disulfide
Cells
Nude Mice
Cell Line
Neoplasms
Gene transfer
Gene therapy
Chemotherapy
Survival
Glutathione Reductase
Heterografts
Genetic Therapy

Keywords

  • Adenovirus
  • BCNU
  • Breast cancer
  • Superoxide dismutase
  • Xenografts

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Increased oxidative stress created by adenoviral MnSOD or CuZnSOD plus BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) inhibits breast cancer cell growth. / Weydert, Christine J.; Zhang, Yuping; Sun, Wenqing; Waugh, Trent A.; Teoh-Fitzgerald, Melissa LT; Andringa, Kelly K.; Aykin-Burns, Nukhet; Spitz, Douglas R.; Smith, Brian J.; Oberley, Larry W.

In: Free Radical Biology and Medicine, Vol. 44, No. 5, 01.03.2008, p. 856-867.

Research output: Contribution to journalArticle

Weydert, Christine J. ; Zhang, Yuping ; Sun, Wenqing ; Waugh, Trent A. ; Teoh-Fitzgerald, Melissa LT ; Andringa, Kelly K. ; Aykin-Burns, Nukhet ; Spitz, Douglas R. ; Smith, Brian J. ; Oberley, Larry W. / Increased oxidative stress created by adenoviral MnSOD or CuZnSOD plus BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) inhibits breast cancer cell growth. In: Free Radical Biology and Medicine. 2008 ; Vol. 44, No. 5. pp. 856-867.
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