Effect of a Single Nucleotide Polymorphism in the Murine Double Minute 2 Promoter (SNP309) on the Sensitivity to Topoisomerase II-Targeting Drugs
A single nucleotide polymorphism (SNP) SNP309 (T–>G) in the murine double minute 2 (MDM2) promoter creates a high-affinity Sp1 binding site and increases the expression of MDM2 mRNA and protein. Approximately 40% of the populations harbor at least one variant allele and 12% to 17% are homozygous G/G at codon 309. This MDM2 SNP increases susceptibility to cancer and decreases the response of cancer cells to certain forms of treatment, such as radiation therapy and DNA-damaging drugs. Topoisomerase II (Topo II)–targeting agents are commonly used chemotherapeutic drugs with a broad spectrum ofactivity. However, resistance to Topo II poisons limits their effectiveness. We show that MDM2 SNP309 rendered a panel of cancer cell lines that are homozygous for SNP309 selectively resistant (f10-fold) to certain Topo II targeting chemotherapeutic drugs (etoposide, mitoxantrone, amsacrine, and ellipticine). The mechanism underlying this observation was Mdm2-mediated down-regulation of Topo II; on drug exposure, MDM2 bound to Topo II and resulted in decreased cellular enzyme content. Knockdown ofMDM2 by RNA interference stabilized Topo IIa and decreased resistance to Topo II-targeting drugs. Thus, MDM2 SNP309 (T–>G) may represent a relatively common, previously unappreciated determinant of drug sensitivity. Given the frequency of SNP309 in the general population (40% in heterozygous T/G and 12% in homozygous G/G condition), our observation may have important implications for the individualization of cancer chemotherapy.
[Cancer Res 2007;67(12):5831–9]
Article Source: Cancer Research Website