p53-independent response of a human breast carcinoma xenograft to radioimmunotherapy

Michelle D. Winthrop, Sally J. DeNardo, Jared T. Muenzer, Sung-Gil Chi, Paul H. Gumerlock

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26 Citations (Scopus)

Abstract

BACKGROUND. Radiation-induced DNA damage resulting in p53 protein attachment and downstream gene activation has been considered a major mechanism for tumor response to low dose rate radiation therapy. In this study, the mechanism of tumor response, and p53 gene status as well as levels of expression of p53 pathway genes were investigated in a human breast rumor (HBT 3477) before and after yttrium-90-DOTA-peptide-ChL6 (Y- 90-ChL6) treatment of these xenografts. METHODS. Mice with HBT 3477 xenografts were treated with 260 μCi Y-90-ChL6 and sacrificed 3, 24 and 48 hours after injection. Reverse transcriptase-polymerase chain reaction and/or Western blotting were used to measure the tumor levels of p53, p21(CDKN1/WAF1) (p21), GADD45, and bcl-2. Single strand conformation polymorphism and direct sequencing were used to determine the mutational status of p53. Evidence of apoptosis was determined by cleavage of poly(ADP-ribose) polymerase (PARP). RESULTS. Tumors regressed 4-7 days after treatment with 260 μCi Y-90-ChL6, resulting in a 79% tumor response. The p53 gene mutation found at codon 342 in HBT 3477 resulted in truncation of the p53 protein, and correlated with undetectable basal p21 protein levels. GADD45 and p53 mRNA decreased after therapy. bcl-2 mRNA was abundant, but decreased. Retinoblastoma phosphorylation showed no changes. Cleavage of PARP was detected at 3 hours and levels were increased greatly at 6 hours after therapy. CONCLUSIONS. Response in the Y-90-ChL6 treated HBT 3477 xenograft tumors was independent of p53 and occurred by apoptosis. The down-regulation of bcl-2 may be the key in this apoptotic response to low dose rate radioimmunotherapy.

Original languageEnglish
Pages (from-to)2529-2537
Number of pages9
JournalCancer
Volume80
Issue number12 SUPPL.
Publication statusPublished - 1997 Dec 15
Externally publishedYes

Keywords

  • Apoptosis
  • Bcl-2
  • Breast carcinoma
  • P53
  • Poly(ADP-ribose) polymerase (PARP)
  • Radioimmunotheraphy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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  • Cite this

    Winthrop, M. D., DeNardo, S. J., Muenzer, J. T., Chi, S-G., & Gumerlock, P. H. (1997). p53-independent response of a human breast carcinoma xenograft to radioimmunotherapy. Cancer, 80(12 SUPPL.), 2529-2537.