Pharmacogenomic identification of targets for adjuvant therapy with the topoisomerase poison camptothecin.
The response of tumor cells to the unusual form of DNA damage caused by topoisomerase poisons such as camptothecin (CPT) is poorly understood, and knowledge regarding which drugs can be effectively combined with CPT is lacking. To better understand the response of tumor cells to CPT and to identify potential targets for adjuvant therapy, we examined global changes in mRNA abundance in HeLa cells after CPT treatment using Affymetrix U133A GeneChips, which include all annotated human genes (22,283 probe sets). Statistical analysis of the data using a Bayesian/Cyber t test and a modified Benjamini and Hochberg correction for multiple hypotheses testing identified 188 probe sets that are induced and 495 that are repressed 8 h after CPT treatment at a False Discovery Rate of <0.05 and a minimum 3-fold change. This pharmacogenomic approach led us to identify two pathways that are CPT induced: (a) the epidermal growth factor receptor; and (b) nuclear factor-kappaB-regulated antiapoptotic factors. Experiments using HeLa cells in our lab and prior animal model studies performed elsewhere confirm that inhibitors of these respective pathways super-additively enhance CPT's cytotoxicity, suggesting their potential as targets for adjuvant therapy with CPT.
Carson
Jonathan P
JP
Department of Genetics and Genomics, Boston University School of Medicine, Boston, Massachusetts, USA.
Zhang
Nianyi
N
Frampton
Garrett M
GM
Gerry
Norman P
NP
Lenburg
Marc E
ME
Christman
Michael F
MF
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000494:pharmacology*; D017024:Chemotherapy, Adjuvant; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics; D015398:Signal Transduction; D059004:Topoisomerase I Inhibitors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D059004:Topoisomerase I Inhibitors; D016159:Tumor Suppressor Protein p53; D002166:Camptothecin