The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38
| Autor: | Stan G. Louie, Melissa J. LaBonte, Philipp C. Manegold, Robert D. Ladner, Will Fazzone, Peter M. Wilson, Heinz-Josef Lenz |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Receptor ErbB-2 medicine.drug_class Colorectal cancer Blotting Western Apoptosis SN-38 Biology Irinotecan Lapatinib Mass Spectrometry Tyrosine-kinase inhibitor Colony-Forming Units Assay Mice chemistry.chemical_compound Stomach Neoplasms Internal medicine Antineoplastic Combined Chemotherapy Protocols Tumor Cells Cultured medicine Animals Humans Epidermal growth factor receptor skin and connective tissue diseases Cell Proliferation Mice Inbred BALB C Cell Cycle Cancer Drug Synergism Flow Cytometry medicine.disease Xenograft Model Antitumor Assays digestive system diseases ErbB Receptors Endocrinology Oncology chemistry Colonic Neoplasms Cancer cell Quinazolines Cancer research biology.protein Camptothecin Chromatography Liquid medicine.drug |
| Zdroj: | International Journal of Cancer. 125:2957-2969 |
| ISSN: | 1097-0215 0020-7136 |
| DOI: | 10.1002/ijc.24658 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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