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

Br J Cancer. 2000 Sep;83(5):594-601. doi: 10.1054/bjoc.2000.1305.

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).

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I

MeSH terms

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

Substances

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