TY - JOUR
T1 - Increased transcriptional activity of prostate-specific antigen in the presence of TNP-470, an angiogenesis inhibitor
AU - Horti, J.
AU - Dixon, S. C.
AU - Logothetis, C. J.
AU - Guo, Y.
AU - Reed, E.
AU - Figg, W. D.
N1 - Funding Information:
This work was supported in part by an unrestricted gift from the F. J. McGuigan Trust, and the Visiting Scholars Program of the EORTC.
PY - 1999
Y1 - 1999
N2 - Prostate-specific antigen, PSA, is regarded as a reliable surrogate marker for androgen-independent prostate cancer (AIPC). Concern has been raised that investigational agents may affect PSA secretion without altering tumour growth or volume. In a phase I trial, several patients with AIPC had elevated serum PSA levels while receiving TNP-470 that reversed upon discontinuation. TNP-470 inhibits capillary growth in several angiogenesis models. These observations prompted us to determine if TNP-470, or its metabolite, AGM-1883, altered PSA secretion. Intracellular protein and transcriptional levels of PSA and androgen receptor were also determined. The highest TNP-470 concentration 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 receptor (AR) transcription was induced 1.2-fold. The increased PSA transcriptional activity accounts for the increased PSA secretion. Increased AR transcription was also reflected at the protein level. In conclusion, TNP-470 and AGM-1883 both up-regulated PSA making clinical utilization of this surrogate marker problematic.
AB - Prostate-specific antigen, PSA, is regarded as a reliable surrogate marker for androgen-independent prostate cancer (AIPC). Concern has been raised that investigational agents may affect PSA secretion without altering tumour growth or volume. In a phase I trial, several patients with AIPC had elevated serum PSA levels while receiving TNP-470 that reversed upon discontinuation. TNP-470 inhibits capillary growth in several angiogenesis models. These observations prompted us to determine if TNP-470, or its metabolite, AGM-1883, altered PSA secretion. Intracellular protein and transcriptional levels of PSA and androgen receptor were also determined. The highest TNP-470 concentration 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 receptor (AR) transcription was induced 1.2-fold. The increased PSA transcriptional activity accounts for the increased PSA secretion. Increased AR transcription was also reflected at the protein level. In conclusion, TNP-470 and AGM-1883 both up-regulated PSA making clinical utilization of this surrogate marker problematic.
KW - AGM-1883
KW - Androgen receptor
KW - Androgen-independent prostate cancer
KW - Prostate-specific antigen
KW - TNP-470
UR - http://www.scopus.com/inward/record.url?scp=0033052655&partnerID=8YFLogxK
U2 - 10.1038/sj.bjc.6690253
DO - 10.1038/sj.bjc.6690253
M3 - Article
C2 - 10188911
AN - SCOPUS:0033052655
SN - 0007-0920
VL - 79
SP - 1588
EP - 1593
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 9-10
ER -