Summary
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.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Abe, J., Zhou, W., Takuwa, N., Taguchi, J., Kurokawa, K., Kumada, M. & Takuwa, Y. (1994). A fumagillin derivative angiogenesis inhibitor, AGM-1470, inhibits activation of cyclin-dependent kinases and phosphorylation of retinoblastoma gene product but not protein tyrosyl phosphorylation or protooncogene expression in vascular endothelial cells. Cancer Res 54: 3407–3412.
Bauer, K. S., Dixon, S. C. & Figg, W. D. (1998). Inhibition of angiogenesis by thalidomide requires metabolic activation with is species-dependent. Biochem Pharmacol 55: 1827–1834.
Figg, W. D., Yeh, H. J. C., Thibault, A., Pluda, J. M., Itoh, F., Yarchoan, R. & Cooper, M. R. (1994). Assay of the antiangiogenic compound, TNP-470, and one of its metabolites, AGM-1883, by reversed-phase high performance liquid chromatography in plasma. J Chrom 652: 187–194.
Figg, W. D., Ammerman, K., Patronas, N., Steinberg, S. M., Walls, R. G., Dawson, N., Reed, E. & Sartor, O. (1996). Lack of correlation between prostate-specific antigen and the presence of measurable soft tissue metastases in hormone-refractory prostate cancer. Cancer Invest 14: 513–517.
Figg, W. D., Bergan, R., Brawley, O., Tompkins, A., Linehan, M., Duray, P., Bauer, K. S., Pluda, J. & Reed, E. (1997a). Randomized phase II study of thalidomide in androgen independent prostate cancer. Proc Am Soc Clin Oncol 16: 1235
Figg, W. D., Pluda, J. M., Lush, R. M., Saville, M. W., Wyvill, K., Reed, E. & Yarchoan, R. (1997b). The pharmacokinetics of TNP-470, a new angiogenesis inhibitor. Pharmacotherapy 1: 91–97.
Folkman, J. & Ingber, D. (1992). Inhibition of angiogenesis. Semin Cancer Biol 3: 89–96.
Ingber, D., Fujita, T., Kishimoto, S., Sudo, K., Kanamary, T., Brem, H. & Folkman, J. (1990). Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature 348: 555–557.
Inoue, K., Korenagea, H., Tanaka, N., Sakamoto, N. & Kadoya, S. (1988). The sulfated polysaccharide-peptidoglycan complex potently inhibits embryonic angiogenesis and tumor growth in the presence of cortisone acetate. Carbohydrate Res 181: 135–142.
Kato, T., Sato, K., Kakinuma, H. & Matsuda, Y. (1994). Enhanced suppression of tumor growth by combination of angiogenesis inhibitor O-(chloroacetyl-carbamoyl) fumagillol (TNP-470) and cytotoxic agents in mice. Cancer Res 54: 5143–5147.
Kelly, W. K., Scher, H. I., Mazumdar, M., Vlamis, V., Schwartz, M. & Fossa, S. D. (1993). Prostate-specific antigen as a measure of disease outcome in metastatic hormone-refractory prostate cancer. J Clin Oncol 11: 607–615.
Kusaka, M., Sudo, K., Fujita, T., Marui, S., Itoh, F., Ingber, D. & Folkman, J. (1991). Potent anti-angiogenic action of AGM-1470: comparison to the fumagillin parent. Biochem Biophys Res Commun 174: 1070–1076.
Logothetis, C. J., Wu, K., Jaeckle, K. A., Amato, R., Finn, L., Weiss, R., Daliani, D., Figg, W. D., Ghaddar, H. & Gutterman, J. (1997). Phase I trial of the angiogenesis inhibitor TNP-470 for progressive androgen-independent prostate cancer. Clin Cancer Res, (submitted)
Lush, R. M., Figg, W. D., Pluda, J. M., Bitton, R., Headlee, D., Kohler, D., Reed, E., Sartor, O. & Cooper, M. R. (1996). A phase I study of pentosan polysulfate sodium in patients with advanced malignancies. Ann Oncol 7: 939–944.
Maione, T. E., Gray, G. S., Petro, J., Hunt, A. J., Donner, A. L., Bauer, S. I., Carson, H. F. & Sharpe, R. J. (1990). Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides. Science 247: 77–79.
Masiero, L., Figg, W. D. & Kohn, E. C. (1997). New anti-angiogenesis agents: review of experience with CAI, thalidomide, TNP-470, and IL-12. Angiogenesis J 1: 23–35.
Matsubara, T., Saura, R., Hirohata, K. & Ziff, M. (1989). Inhibition of human endothelial cell proliferation in vitro and neovascularization in vivo by D-penicillamine. J Clin Invest 83: 158–167.
O’Reilly, M. S., Brem, H. & Folkman, J. (1995). Treatment of murine hemangioendotheliomas with the angiogenesis inhibitor AGM-1470. J Pediatr Surg 30: 325–329.
Sartor, O. (1995). Prostate-specific antigen changes before and after administration of an angiogenesis inhibitor (TNP-470). Oncol Rep 2: 1101–1102.
Sridhara, R., Eisenberger, M. A., Sinibaldi, V., Reyno, L. M. & Egorin, M. J. (1995). Evaluation of prostate-specific antigen as a surrogate marker for response of hormone-refractory prostate cancer to suramin therapy. J Clin Oncol 13: 2944–2953.
Taylor, S. & Folkman, J. (1982). Protamine is an inhibitor of angiogenesis. Nature 297: 307–312.
Thalmann, G. N., Sikes, R. A., Chang, S. M., Johnston, D. A., von Eschenbach, A. C. & Chung, L. W. (1996). Suramin-induced decrease in prostate-specific antigen expression with no effect on tumor growth in the LNCaP model of human prostate cancer. J Natl Cancer Inst 88: 794–801.
Thibault, A., Sartor, O., Cooper, M. R., Figg, W. D. & Myers, C. E. (1993). A 75% decline in prostate specific antigen (PSA) predicts survival in hormone refractory prostate cancer. Proc Am Assoc Cancer Res 34: A1143
Thorpe, P. E., Derbyshire, E. J., Andrade, S. P., Press, N., Knowles, P. P., King, S., Watson, G. J., Yang, Y. C. & Rao-Bette, M. (1993). Heparin-steroid conjugates: new angiogenesis inhibitors with antitumor activity in mice. Cancer Res 53: 3000–3007.
Voest, E. E., Kenyon, B. M., O’Reilly, M. S., Truitt, G., D’Amato, R. J. & Folkman, J. (1995). Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst 87: 581–586.
Walls, R., Thibault, A., Lei, L., Wood, C., Kozlowsky, J. M., Figg, W. D., Sampson, M. L., Elin, R. J. & Samid, D. (1996). The differentiating agent phenylacetate increases prostate-specific antigen production by prostate cancer cells. Prostate 29: 177–182.
Wasilenko, W. J., Palad, A. J., Somers, K. D., Blackmore, P. F., Kohn, E. C., Rhim, J. S., Wright, G. L. Jr & Schellhammer, P. F. (1996). Effects of the calcium influx inhibitor carboxyamido-triazole on the proliferation and invasiveness of human prostate tumor cell lines. Int J Cancer 68: 259–264.
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Horti, J., Dixon, S., Logothetis, C. et al. Increased transcriptional activity of prostate-specific antigen in the presence of TNP-470, an angiogenesis inhibitor. Br J Cancer 79, 1588–1593 (1999). https://doi.org/10.1038/sj.bjc.6690253
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6690253
Keywords
This article is cited by
-
Chemotherapy for advanced prostate cancer: Results of new clinical trials and future studies
Current Oncology Reports (2005)