Platinum (Pt) drugs play a significant role in the clinical management of cancer. The antitumor response caused by Pt agents is believed to be due to Pt-DNA adduct formation. Recent, validated microarray data from this laboratory indicate that both oxaliplatin and cisplatin potently induce gene expression of the key polyamine (PA) catabolic enzyme, spermidine/ spermine N1-acetyltransferase (SSAT), in cultured A2780 ovarian carcinoma cells. Other PA catabolic enzymes were also found to be induced. Since induction of SSAT by other means has been previously linked to growth inhibition and apoptosis, it is likely that the 10-15-fold induction in mRNA seen with oxaliplatin contributes to overall drug action. At clinically achievable drug concentrations and exposure times, oxaliplatin produces a significant induction of SSAT activity due to transcriptional activation of the SSAT gene. The combination of oxaliplatin and N1, N11-diethylnorspermine (DENSPM), a PA analog known to transcriptionally and post-transcriptionally activate SSAT expression, synergistically induces massive amounts of SSAT mRNA and activity and a greater than additive growth inhibition. DENSPM has been shown to be clinically safe and continues to under go clinical testing. The overall goals of this application are to investigate the role of SSAT induction in Pt drug action and to devise therapeutic strategies that exploit synergistic drug interactions at the level of SSAT induction. Thus, specific aims propose to: (1) characterize Pt drug effects alone and in combination with DENSPM on PA metabolism and growth in ovarian cancer cells and Pt drug resistant variants, (2) investigate the mechanistic relationship between PA catabolism and Pt drug action (3) assess the therapeutic potential of the Pt-drug /DENSPM combination against human tumor xenografts. Studies will use biochemical and molecular techniques, novel mouse models, and human tumor xenografts. Overall, we expect to define mechanism-based rationale for clinical trials evaluating the combined use of Pt-drugs and DENSPM.
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