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Targeting slow-proliferating ovarian cancer cells.

Publication ,  Journal Article
Kondoh, E; Mori, S; Yamaguchi, K; Baba, T; Matsumura, N; Cory Barnett, J; Whitaker, RS; Konishi, I; Fujii, S; Berchuck, A; Murphy, SK
Published in: Int J Cancer
May 15, 2010

Advanced ovarian cancer has a high rate of recurrence and mortality despite relative chemosensitivity at the time of initial treatment. Conventional chemotherapeutic agents typically target rapidly dividing cells. Disease relapse may therefore result from the survival and later emergence of latent slow-proliferating and/or quiescent cancer cells. We sought to identify drugs that target this cell population and to investigate the influence of these cells on outcome of patients in remission from advanced ovarian cancer. Drugs with increased efficacy against slower proliferating cells were identified using correlation-based screening of 44,657 compounds tested on the NCI-60 panel of cancer cell lines. Validation of candidates was performed in comparison with Cisplatin or Paclitaxel and by manipulation of proliferation rates by serum deprivation. Cytostatic and cytocidal effects were evaluated using MTT assays and active caspase-3 immunocytochemistry. Ki-67 proliferation indices were determined for tumors from 104 patients in remission. UCN-01 efficacy was correlated with longer doubling time among the NCI-60 cell lines (R = 0.54, p < 0.0001) and in a panel of 24 ovarian cancer cell lines (R = 0.42, p = 0.04), whereas this was not the case for Cisplatin (R = -0.10, p = 0.65) and Paclitaxel efficacy correlated with shorter doubling time (R = -0.52, p = 0.009). Cytostatic and cytocidal effects of UCN-01 were increased in serum-deprived cells. A low proliferation index was associated with presence of persistent disease at second-look surgery (p = 0.01) and poor survival (disease-free survival, p = 0.002; overall survival, p = 0.04). These results suggest that targeting quiescent ovarian cancer cells may be a worthwhile therapeutic approach to improving survival of women with ovarian cancer.

Duke Scholars

Published In

Int J Cancer

DOI

EISSN

1097-0215

Publication Date

May 15, 2010

Volume

126

Issue

10

Start / End Page

2448 / 2456

Location

United States

Related Subject Headings

  • Staurosporine
  • Protein Kinase Inhibitors
  • Protein Kinase C
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Ki-67 Antigen
  • Kaplan-Meier Estimate
  • Immunohistochemistry
  • Humans
  • Female
 

Citation

APA
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ICMJE
MLA
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Kondoh, E., Mori, S., Yamaguchi, K., Baba, T., Matsumura, N., Cory Barnett, J., … Murphy, S. K. (2010). Targeting slow-proliferating ovarian cancer cells. Int J Cancer, 126(10), 2448–2456. https://doi.org/10.1002/ijc.24919
Kondoh, Eiji, Seiichi Mori, Ken Yamaguchi, Tsukasa Baba, Noriomi Matsumura, J. Cory Barnett, Regina S. Whitaker, et al. “Targeting slow-proliferating ovarian cancer cells.Int J Cancer 126, no. 10 (May 15, 2010): 2448–56. https://doi.org/10.1002/ijc.24919.
Kondoh E, Mori S, Yamaguchi K, Baba T, Matsumura N, Cory Barnett J, et al. Targeting slow-proliferating ovarian cancer cells. Int J Cancer. 2010 May 15;126(10):2448–56.
Kondoh, Eiji, et al. “Targeting slow-proliferating ovarian cancer cells.Int J Cancer, vol. 126, no. 10, May 2010, pp. 2448–56. Pubmed, doi:10.1002/ijc.24919.
Kondoh E, Mori S, Yamaguchi K, Baba T, Matsumura N, Cory Barnett J, Whitaker RS, Konishi I, Fujii S, Berchuck A, Murphy SK. Targeting slow-proliferating ovarian cancer cells. Int J Cancer. 2010 May 15;126(10):2448–2456.
Journal cover image

Published In

Int J Cancer

DOI

EISSN

1097-0215

Publication Date

May 15, 2010

Volume

126

Issue

10

Start / End Page

2448 / 2456

Location

United States

Related Subject Headings

  • Staurosporine
  • Protein Kinase Inhibitors
  • Protein Kinase C
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Ki-67 Antigen
  • Kaplan-Meier Estimate
  • Immunohistochemistry
  • Humans
  • Female