Larry M.Weisenthal,Constance M.Weisenthal, Mary E.Smith, Cindy G.Sanchez, and Robin F.Berglund
 

Weisenthal Cancer Group

15140 Transistor Lane

Huntington Beach, CA92649

Phone: 714-894-0011; Fax: 714-893-3658; e-mail:mail@weisenthal.org

 

Supported, in part, by NIH Grant 1R43CA58051-01A1

 

Abstract

 

Background: We examined the relationship between long-term patient survival in ovarian cancer and the results of cell culture drug resistance testing (CCDRT).Methods: The in vitro activity of cisplatin and carboplatin was determined through the concurrent application of two different cell death endpoints (cell membrane dye exclusion/ DISC assay and mitochondrial metabolism/ MTT assay) following 96 hour culture of 3 dimensional microclusters of tumor cells. "Sensitive" / "Intermediate" / "Resistant" cut-offs were defined by calculating means and standard deviations of training set assays performed on a wide variety of human tumors (including non-ovarian tumors) and were reported prospectively.These cut-offs were also re-calculated retrospectively, based only on the datasets of ovarian cancer assays.Results: Specimens from previously-treated patients were significantly more resistant to platinums than were specimens from untreated patients, and this difference was most pronounced in the case of poorly-differentiated tumors.Well-differentiated tumors had significantly greater platinum resistance than poorly-differentiated tumors.In untreated patients (n = 115) resistance to cisplatin and (separately) to carboplatin correlated significantly with long-term survival, as reported prospectively.This relationship was strongest in the case of poorly-differentiated tumors (hazards ratio "sensitive" versus "resistant" =0.31, 95% confidence interval 0.039 - 0.62, for assay results reported prospectively and hazards ratio = 0.22, 95% C.I. 0.043 - 0.47, for cut-offs objectively calculated retrospectively, based on only the ovarian cancer dataset).There was no significant relationship between platinum resistance and patient survival in previously-treated patients (n = 327).Conclusions: Platinum resistance determined by CCDRT using cell death endpoints on tumor cell microclusters predicts for long term survival of untreated ovarian cancer patients with poorly-differentiated tumors.Furthermore, the CCDRT system described here is currently the most highly validated system for studying the circumvention of platinum resistance in human adeno-carcinomas.