Flavopiridol sensitivity of cancer cells isolated from ascites and pleural fluids.
OBJECTIVE
We examined the efficacy of flavopiridol, a cyclin-dependent kinase inhibitor that is undergoing clinical trials, on primary cancer cells isolated from the ascites or pleural fluids of patients with metastatic cancers.


METHODS
Metastasized cancer cells were isolated from the pleural fluids (n = 20) or ascites (n = 15) of patients, most of whom were refractory to chemotherapy. These primary cancer cells were used within 2 weeks of isolation without selecting for proliferative capacities. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assay was used to characterize the response of these cancer cells to commonly used chemotherapeutic agents, and their response to flavopiridol was compared with rapidly dividing cultured cell lines.


RESULTS
The primary cancer cells displayed phenotypes that were different from established cell lines; they had very low replication rates, dividing every 1 to 2 weeks, and underwent replicative senescence within five passages. These primary tumor cells retained their resistance to chemotherapeutic drugs exhibited by the respective patients but did not show cross-resistance to other agents. However, these cancer cells showed sensitivity to flavopiridol with an average LD50 of 50 nmol/L (range, 21.5-69 nmol/L), similar to the LD50 in established cell lines. Because senescent cells also showed similar sensitivity to flavopiridol, it suggests that the mechanism of action is not dependent on the activity of cyclin-dependent kinases that regulate the progression of the cell cycle.


CONCLUSIONS
Using cancer cells isolated from the ascites or pleural fluids, this study shows the potential of flavopiridol against cancer cells that have developed resistance to conventional chemotherapeutic agents.
Richard
Christina
C
Thunder Bay Regional Health Sciences Centre, Thunder Bay, Ontario, Canada.
Matthews
Donald
D
Duivenvoorden
Wilhelmina
W
Yau
Jonathan
J
Wright
Paul S
PS
Th'ng
John P H
JP
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001201:Ascites / Q000473:pathology; D015153:Blotting, Western; D016190:Carboplatin / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D016066:Pleural Effusion, Malignant / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; D019253:Proto-Oncogene Proteins c-bcl-2; C077990:alvocidib; D004317:Doxorubicin; D016190:Carboplatin; D018844:Cyclin-Dependent Kinases; D017239:Paclitaxel; D002945:Cisplatin