Apoptosis-based evaluation of chemosensitivity in ovarian cancer patients.
OBJECTIVE
Induction of apoptosis in target cells is a key mechanism by which chemotherapy induces cell killing. We have established an in vitro system for determining the chemosensitivity of epithelial ovarian cancer cells to carboplatin and paclitaxel (Taxol). Practical assays to predict the likelihood of individual tumor sensitivity are needed to facilitate the choice of adequate treatment. We sought to determine whether epithelial ovarian cancer cells (EOC) collected from the ascites fluid of patients known to be clinically chemosensitive or chemoresistant to carboplatin and paclitaxel would show a similar response to chemotherapeutic drugs after in vitro treatment.


METHODS
Thirteen patients with stage III and IV ovarian cancer treated with carboplatin and paclitaxel were studied. Caspase-3 activation was used as a surrogate marker for activation of chemotherapy-induced programmed cell death. We compared the in vitro apoptotic response to the clinical response of the patients from whom the tumor cells were isolated. Clinical sensitivity was defined as no evidence of disease recurrence for 6 months after optimal debulking surgery and completion of chemotherapy.


RESULTS
Of seven chemosensitive patients, five cell samples treated in vitro had increased caspase-3 activity in response to both carboplatin and paclitaxel. Five of six chemoresistant cases did not show caspase-3 activity in response to only one or to neither agent.


CONCLUSIONS
Quantifiable markers of apoptosis such as caspase-3 activation have the potential to predict the clinical response to chemotherapy. Application of this assay in clinical laboratories could optimize the potential for efficient treatment and avoid the toxicities of ineffective drugs.
Flick
Maryann B
MB
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
O'Malley
David
D
Rutherford
Thomas
T
Rodov
Sofya
S
Kamsteeg
Marijka
M
Hao
Xiao-Ying
XY
Schwartz
Peter
P
Kacinski
Barry M
BM
Mor
Gil
G
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis; D015153:Blotting, Western; D016190:Carboplatin / Q000008:administration & dosage; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D016190:Carboplatin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D017239:Paclitaxel