Abstract
Because tumour cell proliferation is highly dependent upon up-regulation of de-novo polyamine synthesis, inhibition of the polyamine synthesis pathway represents a potential target for anticancer therapy. SAM486A (CGP 48664) is a new inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (SAMDC), more potent and specific than the first-generation SAMDC inhibitor methylglyoxal (bis) guanylhydrazone (MGBG). Preclinical testing confirmed promising antiproliferative activity. In this phase I study, SAM486A was given 4-weekly as a 120 h infusion. 39 adult cancer patients were enrolled with advanced/refractory disease not amenable to established treatments, PS ≤ 2, adequate marrow, liver, renal and cardiac function. Doses were escalated in 100% increments without toxicity in 24 pts from 3 mg m–2 cycle–1 up to 400 mg m–2 cycle–1. At 550 and 700 mg m–2 cycle–1 reversible dose-limiting neutropenia occurred. Other toxicities included mild fatigue, nausea and vomiting. No objective remission was seen. Pharmakokinetic analysis showed a terminal half-life of approximately 2 days. AUC and Cmax were related to dose; neutropenia correlated with AUC. The recommended dose for further phase II studies on this schedule is 400 mg m–2 cycle–1. © 2000 Cancer Research Campaign
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
Degen PH & Zbinden P (1996) Automated quantitative determination of a new polyamine biosynthesis inhibitor (CGP 48664) and a potential metabolite in human and in animal plasma by high-performance liquid chromatography. J Chromatogr 681: 339–345
Delworth MG, Nishioka K, Pettaway C, Gutman M, Killion JJ, von Eschenbach AC & Fidler IJ (1997) Systemic administration of 4-amidinoindanon-1-(2′-amidino)/hydrazone, a new inhibitor of S-adenosylmethionine decarboxylase, produces cytostasis of human prostate cancer in athymic nude mice. Int J Oncology 6: 293–299
Dorhout B, Te Velde RJ, Ferwerda H, Kingma AW, De Hoog E & Muskiet FAJ (1995) In-vivo growth inhibition of L1210 leukemia by 4-amidinoindan-1-one 2′-amidinohydrazone (CGP 48664A), a new inhibitor of S-adenosylmethionine decarboxylase. Int J Cancer 61: 214–217
Greim G, Bruntsch U, Eskens F, Höppener F, Barbet NC, Choi L, Hanauske A-R & Verweij J (1998) Phase I and pharmacologic study of CGP 48664, a SAMDC inhibitor given once weekly × 4 in patients with solid tumors. Proc ASCO 17: 232
Gschaidmeier H, O’Reilly T, Stanek J & Mett H (1999) Additive/synergistic antitumor activity of SAM486A (CGP 48664) combined with cytotoxic drugs in tissue culture and in nude mice. European Concerted Action (COST) Subgroup meeting 917: Bad Nauheim, Germany,
Gutman M, Beltran PJ, Fan D, Delworth M, Singh RK, Wilson M & Fidler IJ (1995) Treatment of nude mice with 4-amidinoindanon-1-(2′-amidino) hydrazone, a new S-adenosylmethionine decarboxylase inhibitor, delays growth and inhibits metastasis of human melanoma cells. Melanoma Research 5: 147–155
Hamacher K, Coenen HH & Stocklin G (1986) Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-D-glucose using aminopolyether supported nucleophilic substitution. J Nucl Med 27: 235–238
Hassels J, Kingma AW, Ferwerda H, Keij J, van den Berg GA & Muskiet FAJ (1989) Microbial flora in the gastrointestinal tract abolishes cytostatic effects of α-difluoromethylornithine in vivo. Int J Cancer 43: 1155–1164
Manni A, Badger B, Wechter R, Kunselman S, Rossini A & Demers L (1995) Biochemical and growth-modulatory effects of the new S-adenosyl methionine decarboxylase inhibitor CGP 48664 in malignant and immortalized normal breast epithelial cells in culture. Int J Cancer 62: 486–491
McCann PP & Pegg AE (1992) Ornithine decarboxylase as an enzyme target for therapy. Pharmacol Ther 54: 195–215
Mi Z, Kramer DL, Miller JT, Bergeron RJ, Bernacki R & Porter CW (1998) Human prostatic carcinoma cell lines display altered regulation of polyamine transport in response to polyamine analogs and inhibitors. The Prostate 34: 51–60
O’Reilly T, Cozens R & Mett H (2000) Evaluation of the antitumor activity of the S-adenosylmethionine decarboxylase (SAMDC) inhibitor SAM486 alone and in combination with conventional cytotoxic agents. American Association for Cancer Research 91st meeting, abstract submitted for publication.
Paridaens R, Uges DRA, Barbet N, Seeghers M, van der Graaf WTA, Lassus M, Groen HJM, Dumez H, Muskiet F, Man A, van Oosterom AT & De Vries EGE (1998) Phase I dose escalation and pharmacokinetic study of CGP 48664, a new S-adenosyl-methionine decarboxylase inhibitor, administered in continuous infusion over 5 days in cancer patients with solid tumors. Proc ASCO 17: 190
Patlak CS, Blasberg RG & Fenstermacher JD (1983) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 3: 1–7
Pegg AE & McCann PP (1992) S-adenosylmethionine decarboxylase as an enzyme target fortherapy. Pharmacol Ther 56: 359–377
Porter CW, Regenass U & Bergeron RJ (1992) Polyamine inhibitors and analogues as potential anticanceragents. In: Polyamines in the gastrointestinal tract, Dowling RH, Fölsch UR Löser R (eds) pp 301–322, Kluwer Academic Publishers: Dordrecht
Porter CW, Siu L, Kramer DL, Mett H, Barbet N, Linnartz R & Eckhardt SG (1998) Pharmacologic confirmation of CGP-48664 as an inhibitor of the polyamine biosynthetic enzyme S-Adenosylmethionine Decarboxylase (SAMDC) in an advanced melanoma patient. 10th NCI-EORTC symposium on new drugs in cancer therapy, June 16–19, 1998 Amsterdam, p 128 abstr. no. 491
Regenass U, Mett H, Stanek J, Mueller M, Kramer D & Porter CW (1994) CGP 48664, a new S-adenosyl methionine decarboxylase inhibitor with broad spectrum antiproliferative and antitumor activity. Cancer Res 54: 3210–3217
Siu LL, Rowinsky EK, Weiss GR, Hammond L, Kraynak M, Moczygemba J, Choi L, Barbet NC, Demoor C, Von Hoff DD & Eckhardt SG (1998) A Phase I and pharmacokinetic study of the polyamine biosynthesis inhibitor CGP 48664 in patients with advanced cancer. Proc ASCO 17: 191
Svensson F, Mett H & Persson L (1997) CGP 48664 a potent and specific S-adenosyl-methionine decarboxylase inhibitor: effects on regulation and stability of the enzyme. Biochemical Journal 322: 297–302
van den Berg GA, Kingman AW & Muskiet FAJ (1987) Determination of polyamines in human erythrocytes by capillary gas chromatography with nitrogen phosphorus detection. J Chromatogr. Biomed. Appl 415: 27–34
Warrell RP & Burchenal JH (1983) Methylglyoxal-bis (guanylhydrazone) (methyl-GAG): current status and future prospects. J Clin Onc 1: 52–65
Woodword HQ, Gigler RE & Freed B (1975) Expression of tissue isotope distribution. J Nucl Med 16: 958–959
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
Paridaens, R., Uges, D., Barbet, N. et al. A phase I study of a new polyamine biosynthesis inhibitor, SAM486A, in cancer patients with solid tumours. Br J Cancer 83, 594–601 (2000). https://doi.org/10.1054/bjoc.2000.1305
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2000.1305
Keywords
This article is cited by
-
AMD1 is required for the maintenance of leukemic stem cells and promotes chronic myeloid leukemic growth
Oncogene (2021)
-
Dual targeting of polyamine synthesis and uptake in diffuse intrinsic pontine gliomas
Nature Communications (2021)
-
mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer
Nature (2017)
-
Discovery of novel inhibitors of human S-adenosylmethionine decarboxylase based on in silico high-throughput screening and a non-radioactive enzymatic assay
Scientific Reports (2015)
-
Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases
Nature Reviews Drug Discovery (2007)