Characterization of sequence-dependent synergy between ZD1839 ('Iressa') and oxaliplatin

被引:48
作者
Xu, JM
Azzariti, A
Severino, M
Lu, B
Colucci, G
Paradiso, A
机构
[1] Natl Canc Inst, Clin Expt Oncol Lab, I-70126 Bari, Italy
[2] Beijing Hosp 307, Ctr Canc, Beijing 100039, Peoples R China
[3] Natl Canc Inst, Gastroenterol Surg Unit, I-70126 Bari, Italy
[4] Beijing Inst Biotechnol, Beijing 100071, Peoples R China
[5] Natl Canc Inst, I-70126 Bari, Italy
关键词
colon cancer; HT-29; LoVo; EGFR-TKI; ZD1839 ('Iressa'); sequence-dependent;
D O I
10.1016/S0006-2952(03)00291-0
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
ZD1839 ('Iressa'), a selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is currently undergoing preclinical and clinical evaluation in several solid tumors. The present study aimed to assess the effect of ZD1839 in combination with oxaliplatin in the colon cancer cell lines HT-29 and LoVo. For in vitro chemosensitivity testing, cells were treated with serial dilutions of each drug sequentially at a fixed ratio of doses that corresponded to 1/20, 1/10, 1/5, 1/2, 1, 1.5 and 2 times the individual IC50 values. Oxaliplatin followed by ZD1839 produced a synergistic effect. In contrast, oxaliplatin following ZD1839 exhibited an additive effect at best. Mass spectrometry examination revealed that ZD1839 modestly enhanced cellular oxaliplatin accumulation and platinum-DNA (Pt-DNA) adducts (P > 0.05). In additional studies, high-performance liquid chromatography revealed that oxaliplatin had no effect on ZD1839 accumulation. In contrast, ZD1839 markedly inhibited removal of Pt-DNA adducts (P < 0.05). With oxaliplatin treatment (1 day) followed by ZD1839 (1 day), then incubation with drug-free medium (1 day), 90% of Pt-DNA adducts remained. Apoptosis examination revealed that oxaliplatin-induced apoptosis was prolonged by sequential oxaliplatin followed by ZD1839 treatment compared with oxaliplatin alone. Further experiments revealed that ZD1839 decreased cellular gamma-glutamyltransferase activity. Conclusions: The above observations provide a mechanistic explanation for the synergy of oxaliplatin followed by ZD1839, and suggest that this treatment combination warrants further preclinical and clinical investigation. (C) 2003 Elsevier Inc. All rights reserved.
引用
收藏
页码:551 / 563
页数:13
相关论文
共 39 条
  • [1] Physical interaction between epidermal growth factor receptor and DNA-dependent protein kinase in mammalian cells
    Bandyopadhyay, D
    Mandal, M
    Adam, L
    Mendelsohn, J
    Kumar, R
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (03) : 1568 - 1573
  • [2] ZD1839 ('Iressa')1,2 as an anticancer agent
    Baselga, J
    Averbuch, SD
    [J]. DRUGS, 2000, 60 (Suppl 1) : 33 - 40
  • [3] Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types
    Baselga, J
    Rischin, D
    Ranson, M
    Calvert, H
    Raymond, E
    Kieback, DG
    Kaye, SB
    Gianni, L
    Harris, A
    Bjork, T
    Averbuch, SD
    Feyereislova, A
    Swaisland, H
    Rojo, F
    Albanell, J
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2002, 20 (21) : 4292 - 4302
  • [4] Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients
    Bécouarn, Y
    Ychou, M
    Ducreux, M
    Borel, C
    Bertheault-Cvitkovic, F
    Seitz, JF
    Nasca, S
    Nguyen, TD
    Paillot, B
    Raoul, JL
    Duffour, J
    Fandi, A
    Dupont-André, G
    Rougier, P
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 1998, 16 (08) : 2739 - 2744
  • [5] Bible KC, 2000, CLIN CANCER RES, V6, P661
  • [6] BRAUN AH, 2002, P AN M AM SOC CLIN, V21, P329
  • [7] QUANTITATIVE-ANALYSIS OF DOSE-EFFECT RELATIONSHIPS - THE COMBINED EFFECTS OF MULTIPLE-DRUGS OR ENZYME-INHIBITORS
    CHOU, TC
    TALALAY, P
    [J]. ADVANCES IN ENZYME REGULATION, 1984, 22 : 27 - 55
  • [8] Ciardiello F, 2001, CLIN CANCER RES, V7, P2958
  • [9] Ciardiello F, 2000, CLIN CANCER RES, V6, P2053
  • [10] Ciardiello F, 2001, CLIN CANCER RES, V7, P1459