Platinum Resistance Determined by Cell Culture Drug Resistance Testing (CCDRT) Predicts for Patient Survival in Ovarian Cancer


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;


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




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.