The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38


Autoria(s): LaBonte, Melissa J; Manegold, Philipp C; Wilson, Peter M; Fazzone, Will; Louie, Stan G; Lenz, Heinz-Josef; Ladner, Robert D; LaBonte Wilson, Melissa
Data(s)

15/12/2009

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

http://pure.qub.ac.uk/portal/en/publications/the-dual-egfrher2-tyrosine-kinase-inhibitor-lapatinib-sensitizes-colon-and-gastric-cancer-cells-to-the-irinotecan-active-metabolite-sn38(ddf5f4b4-c4c1-4b99-afae-6abbc5f22db8).html

http://dx.doi.org/10.1002/ijc.24658

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