Cell-based assays for profiling activity and safety properties of cancer drugs.
BACKGROUND
Our goal was to establish versatile and high capacity assays to characterize activity and toxicity of chemotherapeutics. The major anti-cancer activity indicators of these agents included inhibition of proliferation and induction of apoptosis to cancer cells. In addition, cytotoxicity and myelosuppressive activity to normal cells were parameters to evaluate toxicity of these drugs.


METHODS
Using a panel of cell-based assay systems, we investigated activity and toxicity properties of selected cancer drugs. Drug effects on a number of normal and cancer cell types from human origin were evaluated.


RESULTS
Topoisomerase inhibitors (camptothecin, doxorubicin and etoposide) and microtubule inhibitors (colchicine and paclitaxel) showed anti-proliferation activity and induced apoptosis in MDA-231 cancer cells. Except for doxorubicin, these drugs had relatively low toxicity to normal cells because the dosage required for cytotoxicity EC(50) was >200-folds higher than the dosage for anti-proliferation EC(50) in cancer cells (MDA-231, HL60). However, these drugs were potent inducers of myelotoxicity in human bone marrow progenitor cells. In comparison, the DNA alkylating agents (cisplatin and carboplatin) were less potent proliferation inhibitors (EC(50)>10 microM) in MDA-231 cells and they were also less myelosuppressive.


CONCLUSIONS
Using marketed drugs as examples, our study established a multiple assay platform for profiling in vitro properties of cancer drugs. In drug discovery, such a platform will help to expedite lead selection at early stage.
Li
Weiwei
W
Department of Pharmacology, Berlex Biosciences, Richmond, CA 94804, USA. wei-wei_li@berlex.com
Lam
Marilyn S
MS
Birkeland
Andrew
A
Riffel
Angela
A
Montana
Leticia
L
Sullivan
Mark E
ME
Post
Joseph M
JM