RESUMEN
PURPOSE: The monoclonal antibody pertuzumab represents the first HER2 dimerization inhibitor with unknown activity in colon cancer treatment. We examined the antitumor activity of pertuzumab as a single agent or in combination with erlotinib or irinotecan in human colon cancer cells in vitro and in vivo. METHODS: Colon cancer cell lines were tested for HER1/HER2 expression by western blot analysis. The effect of pertuzumab on cell cycle distribution was analyzed by FACS. Nude mice bearing xenograft tumors were treated with pertuzumab alone, or in combination either with irinotecan or with erlotinib. Tumor volume was measured repeatedly. Tumor histology was analyzed for necrosis. RESULTS: Six of nine cell lines showed high expression of HER1/HER2. Pertuzumab inhibited cell cycle progression in various cell lines. Pertuzumab showed minor antitumor activity in xenograft tumors, but significantly inhibited tumor growth when combined with erlotinib (P < 0.001). Combination of pertuzumab with irinotecan had no additional effect on growth of additional tumors. Pertuzumab treated DLD-1 xenograft tumors did not show enhanced necrosis, which, however, was found in HCT116 derived xenografts. CONCLUSIONS: Pertuzumab has some antitumor activity on human colon cancer cells in vitro and in vivo, in particular when combined with erlotinib. In vivo, pertuzumab combination treatment was not superior to irinotecan monotherapy. These data warrant further investigation of simultaneous HER1/EGFR TKI inhibition and HER1/HER2 dimerization inhibition for colorectal cancer therapy.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Multimerización de Proteína/efectos de los fármacos , Receptor ErbB-2/metabolismo , Animales , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Western Blotting , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Neoplasias Colorrectales/patología , Dimerización , Quimioterapia Combinada , Factor de Crecimiento Epidérmico/farmacología , Clorhidrato de Erlotinib , Femenino , Humanos , Técnicas In Vitro , Irinotecán , Ratones , Ratones Desnudos , Quinazolinas/administración & dosificación , Receptor ErbB-2/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Non-steroidal anti-inflammatory drugs (NSAID) may inhibit colon cancer development through affecting proliferation and apoptosis. However, their use in cancer chemoprevention is still limited due to toxicities. There is longstanding clinical experience with the aminosalicylate mesalazine in the treatment of patients with inflammatory bowel disease with very few side effects. So far, most studies on the cellular effects of mesalazine were focused on its anti-inflammatory properties. Recent data, however, indicate that mesalazine may also reduce cell growth in vivo. We therefore investigated the growth inhibitory effect of mesalazine on human colon cancer cells in vitro compared with established chemopreventive agents. We also wished to determine the underlying cellular mechanisms of the effect. Here we show that mesalazine dose- and time-dependently inhibited the proliferation of colon cancer cells. Mesalazine was less potent in reducing cell growth than sulindac sulfide or indomethacin but growth effective mesalazine concentrations were comparable with concentrations achievable in vivo under standard mesalazine treatment. While other NSAID induced a robust G(1) arrest, mesalazine specifically blocked cells in mitosis although microtubule polymerization or spindle orientation was not affected. In addition, mesalazine induced apoptosis in colon cancer cells possibly through activation of caspase-3 whereas the levels of bcl-2 family proteins were not altered. We conclude that mesalazine inhibits growth of colon cancer cells largely through a mitotic arrest, which has not been reported for NSAID so far. Mesalazine also induces apoptosis through partial activation of caspases similar to, although weaker than, established chemopreventive agents. These findings may suggest a potential of mesalazine as a chemopreventive agent for colorectal cancer.