R. Paridaens et al., A phase I study of a new polyamine biosynthesis inhibitor, SAM486A, in cancer patients with solid tumours, BR J CANC, 83(5), 2000, pp. 594-601
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-adenosylmethionin
e decarboxylase (SAMDC), more potent and specific than the first-generation
SAMDC inhibitor methylglyoxal (bis) guanylhydrazone (MGBG). Preclinical te
sting 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 less than or equal to 2, adequate marrow, liver, renal and c
ardiac function. Doses were escalated in 100% increments without toxicity i
n 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. Othe
r toxicities included mild fatigue, nausea and vomiting. No objective remis
sion was seen. Pharmakokinetic analysis showed a terminal half-life of appr
oximately 2 days. AUG and Cmax were related to dose; neutropenia correlated
with AUG. The recommended dose for further phase II studies on this schedu
le is 400 mg m(-2) cycle(-1). (C) 2000 Cancer Research Campaign.