Abstract | BACKGROUND: METHODS: Two irinotecan-resistant gastric cancer cell lines, OCUM-2M/SN38 and OCUM-8/SN38 were, respectively, established by stepwise exposure to SN38 from the parent gastric cancer cell lines OCUM-2M and OCUM-8. The combination effects of two EGFR inhibitors, gefitinib and lapatinib, with SN38 on proliferation, apoptosis, and cell cycle on gastric cancer cells were examined. RESULTS:
Gefitinib or lapatinib showed synergistic anti-tumour effects against OCUM-2M/SN38 and OCUM-8/SN38 cells when used in combination with SN38, but not against OCUM-2M or OCUM-8 cells. SN38 increased the expression of EGFR and HER2 in OCUM-2M/SN38 and OCUM-8/SN38 cells. The combination of an EGFR inhibitor and SN38 significantly increased the levels of apoptosis-related molecules, caspase-6, p53, and DAPK-2, and resulted in the induction of apoptosis of irinotecan-resistant cells. The EGFR inhibitors increased the S-phase and decreased the UGT1A1 and ABCG expression in irinotecan-resistant cells. The SN38 plus Lapatinib group more effectively suppressed in vivo tumour growth by OCUM-2M/SN38 cells than either alone group. CONCLUSION: The combination treatment with an EGFR inhibitor and irinotecan might produce synergistic anti-tumour effects for irinotecan-refractory gastric cancer cells. The regulation of SN38 metabolism-related genes and cell cycle by EGFR inhibitors might be responsible for the synergism.
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Authors | M Yashiro, H Qiu, T Hasegawa, X Zhang, T Matsuzaki, K Hirakawa |
Journal | British journal of cancer
(Br J Cancer)
Vol. 105
Issue 10
Pg. 1522-32
(Nov 08 2011)
ISSN: 1532-1827 [Electronic] England |
PMID | 21997136
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | 2011 Cancer Research UK |
Chemical References |
- Quinazolines
- Lapatinib
- Irinotecan
- ErbB Receptors
- Gefitinib
- Camptothecin
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Topics |
- Animals
- Apoptosis
(drug effects)
- Camptothecin
(analogs & derivatives, pharmacology)
- Cell Cycle
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Drug Screening Assays, Antitumor
- Drug Synergism
- ErbB Receptors
(antagonists & inhibitors, genetics)
- Gefitinib
- Genes, erbB-2
- Humans
- Irinotecan
- Lapatinib
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Quinazolines
(pharmacology)
- Stomach Neoplasms
(pathology)
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