Antisense MDM2 oligonucleotides restore the apoptotic response of prostate cancer cells to androgen deprivation

Abstract

Purpose/Objective: Androgen deprivation (AD) alone or in combination with radiotherapy is the most common therapy for high risk prostate cancer. Early in the malignant transformation of prostate epithelial cells, the apoptotic response to AD is lost and the principal response is a slowing of cell growth. While the combination of AD+RT has been shown to result in supra-additive apoptosis, this response is minor and is not the major mechanism associated with the improved results from the AD+RT over RT alone. The hypothesis is that restoring the apoptotic response prostate cancer cells to AD through manipulation of the intracellular molecular milieu would first, reduce the number of clonogens that RT would need to eliminate and second, direct cells subsequently treated with RT down the apoptotic pathway in a supra-additive manner such that ultimate cell killing would be greatly enhanced. The MDM2 protein is a negative feedback regulator of p53 function and is overexpressed in many prostate cancers. The data described show that interruption of MDM2 function using antisense MDM2 oligonucleotide (AS-MDM2) restores the apoptotic response of prostate cancer cells to AD.