Evaluation of Topoisomerase II Isoform Expression as a Determinant of Tumor Cell Response to Topoisomerase II Targeted Drugs Using a Novel RNA-PCR Assay

Abstract

Topoisomerase II (topo II) gene expression has been implicated in predicting the response of tumor cells to a number of topo II targeted agents. Two distinct isoforms, a and p, have different biological and pharmacological properties. The Polymerase Chain Reaction (PCR) was utilized to estimate the expression level of both isoforms in a disease-oriented human tumor cell line panel. Topo II expression was standardized to two reference genes and measured in two independent PCR reactions. The quantity of isoform expression and ratio was correlated with dose response data from three topo II targeted agents and three control non-topo II targeted agents. Cell lines were evaluated collectively and by disease type. Correlation analysis demonstrated an insignificant relationship between response to the selected drugs and topo II isoform expression, as estimated by mRNA amplification. Therefore, relative resistance to topo II targeted drugs appears not to be directly related to the level of transcript. Post-transcriptional or post-translational factors may be important in defining an altered topo II multidrug resistant phenotype. Alternatively, cell physiological or other forms of drug resistance may have predominant importance.