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

J. Horti, S. C. Dixon, C. J. Logothetis, Y. Guo, E. Reed, W. D. Figg

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1588-1593
Number of pages6
JournalBritish journal of cancer
Volume79
Issue number9-10
DOIs
StatePublished - Jan 1 1999

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Keywords

  • AGM-1883
  • Androgen receptor
  • Androgen-independent prostate cancer
  • Prostate-specific antigen
  • TNP-470

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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