Abberations in Phospholipase D Activity‐A Pharmacological Target for Cancer Detection

Abstract

Understanding molecular targets and developing novel molecular imaging agents can improve early cancer detection. Radioiodinated NM404, a phospholipid ether analog in clinical trials, displays selective and prolonged retention in 28/28 xenograft and spontaneous tumor models. This specificity for malignant tumors is apparently due to prolonged and selective retention of NM404 in cancer cells having reduced ability to metabolize NM404. Prior in vitro studies implicate phospholipase D (PLD) in NM404 metabolism. PLD is a critical regulator of cell proliferation, survival signaling, cell transformation and tumor progression. Decreased expression of PLD in numerous tumors has been reported, and thus, reduced PLD levels in malignant cells may result in prolonged retention of NM404. PLD activity and expression were evaluated to assess the mechanism of action of NM404 and possibly identify novel drug development targets. Fluorescent enzyme assay and RT-PCR were used to quantify PLD in mouse and human malignant cell lines and solid tumors compared to normal host tissue. PLD activity and mRNA levels were significantly lower (p<0.05, T-test) in malignant cells compared to the respective normal host tissues. The data strongly suggest decreased PLD activity in malignant cells may result in selective retention of NM404 and that malignancy maybe associated with aberrations in PLD activity. Supported by NCI grant CA95240