Targeting slow-proliferating ovarian cancer cells.
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.
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University, Durham, NC 27708, USA.
Eiji
E
Kondoh
Seiichi
S
Mori
Ken
K
Yamaguchi
Tsukasa
T
Baba
Noriomi
N
Matsumura
J
J
Cory Barnett
Regina S
RS
Whitaker
Ikuo
I
Konishi
Shingo
S
Fujii
Andrew
A
Berchuck
Susan K
SK
Murphy
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3 / Q000032:analysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D054697:Cytostatic Agents / Q000494:pharmacology*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D054697:Cytostatic Agents; D019394:Ki-67 Antigen; D047428:Protein Kinase Inhibitors; C054852:7-hydroxystaurosporine; D011493:Protein Kinase C; D053148:Caspase 3; D019311:Staurosporine