The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38
Data(s) |
15/12/2009
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Resumo |
<p>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.</p> |
Identificador | |
Idioma(s) |
eng |
Direitos |
info:eu-repo/semantics/restrictedAccess |
Fonte |
LaBonte , M J , Manegold , P C , Wilson , P M , Fazzone , W , Louie , S G , Lenz , H-J , Ladner , R D & LaBonte Wilson , M 2009 , ' The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38 ' International journal of cancer. Journal international du cancer , vol 125 , no. 12 , pp. 2957-69 . DOI: 10.1002/ijc.24658 |
Palavras-Chave | #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 |
Tipo |
article |