The Interactive Transcript Abundance Index [c-myc*p73á]/[p21*Bcl-2] Correlates With Spontaneous Apoptosis and Response to CPT-11: Implications for Predicting Chemoresistance and Cytotoxicity to DNA Damaging Agents
Cytotoxic and targeted therapies are ineffective in the majority of individuals diagnosed with bronchogenic carcinoma, due in part, to alterations in genes that regulate cell proliferation control and apoptosis. In order to develop more effective therapies, and better utilize existing therapies, it is necessary to understand how inter-individual variation in gene expression contributes to therapeutic response, so that each individual receives the appropriate medication at the appropriate dose. First, we found extensive inter-individual variation in the expression of the cyclin-dependent kinase inhibitor, p21, which was attributable to upstream transcription factors E2F1 and p73 in bronchogenic carcinoma cells, but not normal bronchial epithelial cells. Second, we hypothesized that bronchogenic carcinoma cell lines with high expression of E2F1 and p73, and wild type p53, would have a defect in their apoptosis pathway, and therefore, would be resistant to chemotherapy. However, high expression of E2F1 and p73 as well as c-myc, was associated with spontaneous apoptosis and chemosensitivity, but induction of p53 and p21 was associated with small increases in apoptosis and chemoresistance. From these results we identified an interactive transcript abundance index (ITAI) in the form of a ratio, [c-myc*p73á]/[p21*Bcl-2] which was correlated with response to CPT-11 in bronchogenic carcinomas and other tissues, regardless of p53 status. These studies lead to an additional hypothesis, that inter-individual variation in expression of p53 and related genes in peripheral blood leukocytes (PBLs) could predict cytotoxicity to chemotherapy. In these studies, variation in gene expression was observed between two individuals that showed vast differences in lymphocyte counts following chemotherapy. In summary, we have identified at set of genes that contribute to cell proliferation control and apoptosis in normal and malignant cells, and may collectively predict chemoresistance or cytotoxicity. The use of expression profiling in this context will increase the efficacy of currently available mediations, while minimizing adverse side effects, and will facilitate the development of newer therapies that target specific genetic defects.
School:University of Toledo Health Science Campus
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:chemoresistance p53 cpt 11 irinotecan apoptosis lung cancer
Date of Publication:01/01/2006