Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148):: a polymeric derivative of camptothecin (CPT)

被引:85
作者
Bissett, D
Cassidy, J
de Bono, JS
Muirhead, F
Main, M
Robson, L
Fraier, D
Magnè, ML
Pellizzoni, C
Porro, MG
Spinelli, R
Speed, W
Twelves, C
机构
[1] Univ Aberdeen, Aberdeen Royal Infirm, Dept Med Oncol, Aberdeen AB25 2ZN, Scotland
[2] Univ Glasgow, Dept Med Oncol, Beatson Oncol Ctr, Western Infirm, Glasgow G11 6NT, Lanark, Scotland
[3] Canc Res UK, Drug Dev Off, London, England
[4] Pharmacia & Upjohn Inc, Nerviano, Italy
关键词
MAG-CPT; polymeric; camptothecin; pharmacokinetics;
D O I
10.1038/sj.bjc.6601922
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Polymeric cytotoxic conjugates are being developed with the aim of preferential delivery of the anticancer agent to tumour. MAG-CPT comprises the topoisomerase I inhibitor camptothecin linked to a water-soluble polymeric backbone methacryloylglycynamide ( average molecular weight 18 kDa, 10% CPT by weight). It was administered as a 30-min infusion once every 4 weeks to patients with advanced solid malignancies. The objectives of our study were to determine the maximum tolerated dose, dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document responses to this treatment. The starting dose was 30 mgm(-2) (dose expressed as mg equivalent camptothecin). In total, 23 patients received 47 courses at six dose levels, with a maximum dose of 240 mgm(-2). Dose-limiting toxicities were myelosuppression, neutropaenic sepsis, and diarrhoea. One patient died after cycle 1 MAG-CPT at the maximum dose. The maximum tolerated dose and dose recommended for further clinical study was 200 mgm(-2). The half-lives of both MAG-CPT and released CPT were prolonged (46 days) and measurable levels of MAG-CPT were retrieved from plasma and urine 4 weeks after treatment. However, subsequent pharmacodynamic studies of this agent have led to its withdrawal from clinical development.
引用
收藏
页码:50 / 55
页数:6
相关论文
共 13 条
[1]   Polymer-bound camptothecin: initial biodistribution and antitumour activity studies [J].
Caiolfa, VR ;
Zamai, M ;
Fiorino, A ;
Frigerio, E ;
Pellizzoni, C ;
d'Argy, R ;
Ghiglieri, A ;
Castelli, MG ;
Farao, M ;
Pesenti, E ;
Gigli, M ;
Angelucci, F ;
Suarato, A .
JOURNAL OF CONTROLLED RELEASE, 2000, 65 (1-2) :105-119
[2]   Camptothecin delivery systems: enhanced efficacy and tumor accumulation of camptothecin following its conjugation to polyethylene glycol via a glycine linker [J].
Conover, CD ;
Greenwald, RB ;
Pendri, A ;
Gilbert, CW ;
Shum, KL .
CANCER CHEMOTHERAPY AND PHARMACOLOGY, 1998, 42 (05) :407-414
[3]  
Conover CD, 1999, ANTI-CANCER DRUG DES, V14, P499
[4]   Polymer-drug conjugates, PDEPT and PELT: basic principles for design and transfer from the laboratory to clinic [J].
Duncan, R ;
Gac-Breton, S ;
Keane, R ;
Musila, R ;
Sat, YN ;
Satchi, R ;
Searle, F .
JOURNAL OF CONTROLLED RELEASE, 2001, 74 (1-3) :135-146
[5]  
GOTTLIEB JA, 1970, CANCER CHEMOTH REP 1, V54, P461
[6]  
MATSUMURA Y, 1986, CANCER RES, V46, P6387
[7]  
MUGGIA FM, 1972, CANCER CHEMOTH REP 1, V56, P515
[8]   Molecular, cellular, and clinical aspects of the pharmacology of 20(S)camptothecin and its derivatives [J].
Rivory, LP ;
Robert, J .
PHARMACOLOGY & THERAPEUTICS, 1995, 68 (02) :269-296
[9]   Assessment of normal and tumor tissue uptake of MAG-CPT, a polymer-bound prodrug of camptothecin, in patients undergoing elective surgery for colorectal carcinoma [J].
Sarapa, N ;
Britto, MR ;
Speed, W ;
Jannuzzo, M ;
Breda, M ;
James, CA ;
Porro, M ;
Rocchetti, M ;
Wanders, A ;
Mahteme, H ;
Nygren, P .
CANCER CHEMOTHERAPY AND PHARMACOLOGY, 2003, 52 (05) :424-430
[10]   A phase I and pharmacokinetic study of MAG-CPT, a water-soluble polymer conjugate of camptothecin [J].
Schoemaker, NE ;
van Kesteren, C ;
Rosing, H ;
Jansen, S ;
Swart, M ;
Lieverst, J ;
Fraier, D ;
Breda, M ;
Pellizzoni, C ;
Spinelli, R ;
Porro, MG ;
Beijnen, JH ;
Schellens, JHM ;
Huinink, WWT .
BRITISH JOURNAL OF CANCER, 2002, 87 (06) :608-614