A phase I study of a new polyamine biosynthesis inhibitor, SAM486A, in cancer patients with solid tumours.

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).

• Authors: R Paridaens, D R Uges, N Barbet, L Choi, M Seeghers, W T van der Graaf, H J Groen, H Dumez, I V Buuren, F Muskiet, R Capdeville, A T Oosterom, E G de Vries
• Journal: British journal of cancer (Br J Cancer) Vol. 83 Issue 5 Pg. 594-601 (Sep 2000) ISSN: 0007-0920 [Print] England
• PMID: 10944598 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)
• Copyright: Copyright 2000 Cancer Research Campaign.

Chemical References

• Amidines
• Antimetabolites, Antineoplastic
• Antineoplastic Agents
• Indans
• Polyamines
• Radiopharmaceuticals
• Fluorodeoxyglucose F18
• 4-amidinoindan-1-one 2'-amidinohydrazone
• Adenosylmethionine Decarboxylase
• Fluorouracil

Topics

• Adenosylmethionine Decarboxylase (antagonists & inhibitors)
• Adult
• Aged
• Agranulocytosis (chemically induced)
• Amidines (adverse effects, pharmacokinetics, therapeutic use)
• Antimetabolites, Antineoplastic (therapeutic use)
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Area Under Curve
• Dose-Response Relationship, Drug
• Female
• Fluorodeoxyglucose F18
• Fluorouracil (therapeutic use)
• Humans
• Indans (adverse effects, pharmacokinetics, therapeutic use)
• Male
• Middle Aged
• Neoplasms (drug therapy)
• Polyamines (chemistry, metabolism)
• Radiopharmaceuticals
• Time Factors
• Tomography, Emission-Computed