Abstract
Members of the human epidermal receptor (HER) family are frequently associated with aggressive disease and poor prognosis in multiple malignancies. Lapatinib is a dual tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) and HER-2. This study evaluated the therapeutic potential of lapatinib, alone and in combination with SN-38, the active metabolite of irinotecan (CPT-11), in colon and gastric cancer cell lines. Concentration-dependent antiproliferative effects of both lapatinib and SN-38 were observed in all colon and gastric cancer cell lines tested but varied significantly between individual cell lines (lapatinib range 0.08-11.7 muM; SN-38 range 3.6-256 nM). Lapatinib potently inhibited the growth of a HER-2 overexpressing gastric cancer cell line and demonstrated moderate activity in gastric and colon cancer cells with detectable HER-2 expression. The combination of lapatinib and SN-38 interacted synergistically to inhibit cell proliferation in all colon and gastric cancer cell lines tested. Cotreatment with lapatinib and SN-38 also resulted in enhanced cell cycle arrest and the induction of apoptosis with subsequent cellular pharmacokinetic analysis demonstrating that lapatinib promoted the increased intracellular accumulation and retention of SN-38 when compared to SN-38 treatment alone. Finally, the combination of lapatinib and CPT-11 demonstrated synergistic antitumor efficacy in the LoVo colon cancer mouse xenograft model with no apparent increase in toxicity compared to CPT-11 monotherapy. These results provide compelling preclinical rationale indicating lapatinib to be a potentially efficacious chemotherapeutic combination partner for irinotecan in the treatment of gastrointestinal carcinomas.
Original language | English |
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Pages (from-to) | 2957-69 |
Number of pages | 13 |
Journal | International journal of cancer. Journal international du cancer |
Volume | 125 |
Issue number | 12 |
DOIs | |
Publication status | Published - 15 Dec 2009 |
Bibliographical note
Copyright (c) 2009 UICC.Keywords
- Animals
- Antineoplastic Combined Chemotherapy Protocols
- Apoptosis
- Blotting, Western
- Camptothecin
- Cell Cycle
- Cell Proliferation
- Chromatography, Liquid
- Colonic Neoplasms
- Colony-Forming Units Assay
- Drug Synergism
- Flow Cytometry
- Humans
- Male
- Mass Spectrometry
- Mice
- Mice, Inbred BALB C
- Quinazolines
- Receptor, Epidermal Growth Factor
- Receptor, ErbB-2
- Stomach Neoplasms
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays