Increased transcriptional activity of prostate-specific antigen in the presence of TNP-470, an angiogenesis inhibitor

Prostate-specific antigen, PSA, is regarded as a reliable surrogate marker for androgen-independent prostate cancer (AIPC). Concern has been raised th at investigational agents may affect PSA secretion without altering tumour growth or volume. In a phase I trial, several patients with AIPC had elevat ed serum PSA levels while receiving TNP-470 that reversed upon discontinuat ion. TNP-470 inhibits capillary growth in several angiogenesis models. Thes e observations prompted us to determine if TNP-470, or its metabolite, AGM- 1883, altered PSA secretion. Intracellular protein and transcriptional leve ls of PSA and androgen receptor were also determined. The highest TNP-470 c oncentration produced a 40.6% decrease in cell number; AGM-1883 had minimal effects on cell viability. PSA secretion per cell was induced 1.1- to 1.5- fold following TNP-470 exposure. The same trend was observed for AGM-1883. PSA and AR were transcriptionally upregulated within 30 min after exposure to TNP-470. PSA transcription was increased 1.4-fold, while androgen recept or (AR) transcription was induced 1.2-fold. The increased PSA transcription al activity accounts for the increased PSA secretion. Increased AR transcri ption was also reflected at the protein level. In conclusion, TNP-470 and A GM-1883 both up-regulated PSA making clinical utilization of this surrogate marker problematic.