TY - JOUR
T1 - Characterization of sequence-dependent synergy between ZD1839 ('Iressa') and oxaliplatin
AU - Xu, Jian Ming
AU - Azzariti, Amalia
AU - Severino, Montemuro
AU - Lu, Bing
AU - Colucci, Giuseppe
AU - Paradiso, Angelo
PY - 2003/8/15
Y1 - 2003/8/15
N2 - 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 IC
50 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
AB - 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 IC
50 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
KW - Colon cancer
KW - EGFR-TKI
KW - HT-29
KW - LoVo
KW - Sequence-dependent
KW - ZD1839 ('Iressa')
UR - http://www.scopus.com/inward/record.url?scp=0142071058&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0142071058&partnerID=8YFLogxK
U2 - 10.1016/S0006-2952(03)00291-0
DO - 10.1016/S0006-2952(03)00291-0
M3 - Article
C2 - 12906920
AN - SCOPUS:0142071058
VL - 66
SP - 551
EP - 563
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 4
ER -