The interactive transcript abundance index [c-myc*p73alpha]/[p21*Bcl-2] correlates with baseline level of apoptosis and response to CPT-11 in human bronchogenic carcinoma cell lines.
Currently available cytotoxic chemotherapy is ineffective for treating bronchogenic carcinoma, and this is partly due to unpredictable inter-tumor variation in resistance. For example, tumors with inactivating p53 mutations or deletions are less likely to respond to certain chemotherapeutics. However, even if p53 is intact, a tumor may be unresponsive if defects in other p53 pathway genes compromise apoptosis. In an effort to identify biomarkers that better predict response to camptothecin, we investigated the association of CPT-11 (irinotecan)-induced cytotoxicity (IC50) with apoptosis or expression of genes upstream or downstream of p53 in cell lines that retain wild-type p53. CPT-11 response was greater in cell lines with higher baseline apoptosis (p<0.05). In addition, the interactive transcript abundance index (ITAI) [c-myc*p73alpha]/[p21*Bcl-2] was directly correlated with baseline apoptosis (p<0.01) and CPT-11 response (p<0.05). The ITAI was also correlated with CPT-11 response among cell lines derived from a variety of tissues that had inactivating p53 mutations or deletions, supporting its applicability for predicting response to camptothecins in other tissues regardless of p53 status.
Harr
Michael W
MW
Department of Medicine, University of Toledo, Health Science Campus, Toledo, OH 43614, USA.
Willey
James C
JC
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002283:Carcinoma, Bronchogenic / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012322:RNA Precursors; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; C489427:MYC protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D012322:RNA Precursors; D000077146:Irinotecan; D002166:Camptothecin