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 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 up-regulated 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.
Horti
J
J
Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, Maryland 20892, USA.
Dixon
S C
SC
Logothetis
C J
CJ
Guo
Y
Y
Reed
E
E
Figg
W D
WD
D000081:Acetamides / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002452:Cell Count / Q000187:drug effects; D003510:Cyclohexanes; D006801:Humans; D008297:Male; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D017430:Prostate-Specific Antigen / Q000187:drug effects* / Q000378:metabolism; D011944:Receptors, Androgen / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000081:Acetamides; D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D011944:Receptors, Androgen; D012717:Sesquiterpenes; D013141:Spiro Compounds; C087809:AGM 1883; D017430:Prostate-Specific Antigen; D000077609:O-(Chloroacetylcarbamoyl)fumagillol