Drug Discovery Opinion

The retrovirus, xenotropic murine leukemia virus-related virus (XMRV), has been – controversially – linked to both prostate cancer and chronic fatigue syndrome (CFS). In an attempt to clarify the association of XMRV with disease, researchers at Emory University are developing a serum-based assay to detect neutralising antibodies to the virus which should begin to answer basic questions about how widespread the virus is, and how it is transmitted. The team found good agreement between their serum based assay and polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH) tests carried out on prostate samples from cancer patients, and showed that at least some of the patients had been infected with XMRV. The study is published in the April issue of Urology.

Meanwhile, other researchers at Emory University/Atlanta Veterans Affairs Medical Center and the University of Utah have been looking for ways to treat XMRV should it turn out to have a causal role in prostate cancer or chronic fatigue syndrome. The team evaluated 45 compounds, mostly drugs approved for the treatment of HIV/AIDS, and found that four of them were able to inhibit XMRV with EC₅₀ values of < 1µM. XMRV replication was studied in both MCF-7 cells (generated from human breast cancer) and LNCaP cells (generated from human prostate cancer). The most effective compounds were two nucleoside reverse transcriptase inhibitors (zidovudine and tenofovir disoproxil fumarate) and two integrase inhibitors (raltegravir and L-000870812). Despite the lack of homology (only 14% identity) between HIV-1 integrase and XMRV integrase, raltegravir showed particularly good activity against XMRV with EC₅₀ values of 0.005µM and 0.03µM in MCF-7 and LNCaP cells respectively (cf 0.001µM for HIV-1 grown in PBMCs). The EC₉₀/EC₅₀ ratio was significantly higher for XMRV grown in MCF-7 cells than for XMRV grown in LNCaP cells or for HIV-1 grown in PBMCs (700, 15 and 9 respectively). Synergy studies were carried out in LNCaP cells: combinations of raltegravir and any of the other three compounds were found to act synergistically.

The authors hope that if XMRV is established as a cause of prostate cancer or CFS, existing HIV treatments may prove to be effective therapies for these conditions.

The study is published in PLoS ONE.

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