[Experimental study of effect of epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in combination with irinotecan].
OBJECTIVE
To assess the optimal regimen and its mechanism of ZD1839 in combination with SN38, the active metabolite of irinotecan (CPT-11), in the colon cancer cell lines HT-29 and LoVo.


METHODS
Chou and Talalay method was used to analyze the combination effects of sequencing of ZD1839 and SN38. Western blotting and immunoprecipitation were used to determine the effects of ZD1839 and/or SN38 on their targeted enzymes and downstream markers. Apoptosis was assayed by analyzing histone-associated DNA fragment.


RESULTS
Sequential SN38 followed by ZD1839 produced a synergistic effect. In contrast, SN38 following ZD1839 exhibited an antagonist effect. SN38 markedly inhibited topoisomerase I (Topo-I) activity. ZD1839 did not alter epidermal growth factor receptor (EGFR) expression, but resulted in a complete inhibition of EGFR phosphorylation. Sequential ZD1839 followed by SN38 did not show any enhanced inhibition effect on Topo-I activity, phosphorylation of EGFR and one of its downstream markers MAPK. However, simultaneous SN38 plus ZD1839, and sequential SN38 followed by ZD1839 administrations showed modest inhibition effect on EGFR's another downstream marker AKT. The combination schedules also showed prominent influence on cell cycle distribution. ZD1839 maintained SN38-induced DNA damage and apoptosis.


CONCLUSIONS
Sequential SN38 followed by ZD1839 may be a favorable combination schedule.
Xu
Jian-ming
JM
Beijing 307 Hospital Cancer Center, Beijing 100071, China. jmxu2003@yahoo.com
Li
Yue-min
YM
Wang
Yan
Y
Zhao
Chuan-hua
CH
Yuan
Shou-jun
SJ
Yang
Wu-wei
WW
Li
Zhi-qiang
ZQ
Han
Yu
Y
Azzariti
Amalia
A
Paradiso
Angelo
A
D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077156:Gefitinib; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D000077146:Irinotecan; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D011799:Quinazolines; D000077146:Irinotecan; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D004264:DNA Topoisomerases, Type I; D000077156:Gefitinib; D002166:Camptothecin