A phase I study of a new polyamine biosynthesis inhibitor, SAM486A, in cancer patients with solid tumours.
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).
Paridaens
R
R
Universitair Ziekenhuis Gasthuisberg, Herestraat 49, Leuven, 3000, Belgium.
Uges
D R
DR
Barbet
N
N
Choi
L
L
Seeghers
M
M
van der Graaf
W T
WT
Groen
H J
HJ
Dumez
H
H
Buuren
I V
IV
Muskiet
F
F
Capdeville
R
R
Oosterom
A T
AT
de Vries
E G
EG
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors*; D000328:Adult; D000368:Aged; D000380:Agranulocytosis / Q000139:chemically induced; D000578:Amidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D019788:Fluorodeoxyglucose F18; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D007189:Indans / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011073:Polyamines / Q000737:chemistry / Q000378:metabolism*; D019275:Radiopharmaceuticals; D013997:Time Factors; D014055:Tomography, Emission-Computed
D000578:Amidines; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D007189:Indans; D011073:Polyamines; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; C082408:4-amidinoindan-1-one 2'-amidinohydrazone; D012437:Adenosylmethionine Decarboxylase; D005472:Fluorouracil