INHIBITION OF CYCLIC AMP-TRIGGERED AROMATASE GENE-EXPRESSION IN HUMANCHORIOCARCINOMA CELLS BY ANTISENSE OLIGODEOXYNUCLEOTIDE

Aromatase, an endomembrane-bound cytochrome P450, is the key enzyme of estrogen biosynthesis. Aromatase inhibitors, therefore, are clinicall y important tools in the treatment of estrogen-dependent tumor growth. To improve the specificity of these tools, inhibition at the nucleic acid level was examined. An antisense oligodeoxynucleotide complementa ry to the translation start region of human aromatase transcripts (ant isense-arom) was synthesized and used to inhibit cyclic AMP-triggered aromatase gene expression in a human choriocarcinoma cell line (JEG-3) , both as occurring in an autocrine fashion by secreted human chorioni c gonadotropin or as induced by application of the membrane-permeating dibutyryl cyclic AMP. Significant inhibition was obtained in both cas es, reaching 70% and 60%, respectively. In addition, the antisense-aro m treatment led to accelerated mRNA degradation. The inhibition at the nucleic acid level, was accompanied by a decrease of both the aromata se protein and microsomal aromatase activity. The data appear to indic ate the antisense strategy to be a most promising approach for the dev elopment of a novel type of specific aromatase inhibitor.