Schedule-dependent antitumor activity of the combination with erlotinib and docetaxel in human non-small cell lung cancer cells with EGFR mutation, KRAS mutation or both wild-type EGFR and KRAS.
ABSTRACT Erlotinib is used as a standard treatment for recurrent advanced non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutations in NSCLC have been shown to be a predictive factor of erlotinib, although the relationship between K-ras oncogene (KRAS) mutations and erlotinib resistance is controversial. Recently, in vitro sequence-dependent interactions of erlotinib and docetaxel have been studied on as a novel therapeutic approach against NSCLC. The purpose of the present study was to determine the optimum novel regimen of erlotinib and docetaxel against NSCLC cells which have EGFR mutation (HCC827 cells), KRAS mutation (A549 cells) or both wild-type (NCI-H292 cells). First, we analyzed the effects of in vitro combination for cell proliferation-inhibition using a combination index. In all cell lines, docetaxel followed by erlotinib treatment showed nearly additive effects. On the other hand, erlotinib followed by docetaxel treatment showed remarkable antagonistic interactions. Second, we examined the effect of combinations on the in vitro apoptosis induction. Erlotinib followed by docetaxel treatment reduced apoptosis induction compared with docetaxel alone; in contrast, docetaxel followed by erlotinib treatment had no inhibitory effects on docetaxel-induced apoptosis in any of the cell lines. Finally, an in vivo tumor growth inhibition test was performed using xenograft models. Docetaxel followed by erlotinib administration resulted in significant tumor growth inhibition compared with erlotinib or docetaxel monotherapy in all models. In conclusion, we demonstrated that docetaxel followed by erlotinib therapy was a potentially optimum regimen against NSCLC regardless of the mutation status of EGFR and KRAS.
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ABSTRACT: The MUC1-C oncoprotein is aberrantly expressed in most multiple myeloma cells. However, the functional significance of MUC1-C expression in multiple myeloma is not known. The present studies demonstrate that treatment of multiple myeloma cells with a MUC1-C inhibitor is associated with increases in reactive oxygen species (ROS), oxidation of mitochondrial cardiolipin, and loss of the mitochondrial transmembrane potential. The MUC1-C inhibitor-induced increases in ROS were also associated with down-regulation of the p53-inducible regulator of glycolysis and apoptosis (TIGAR). In concert with the decrease in TIGAR expression, which regulates the pentose phosphate pathway, treatment with the MUC1-C inhibitor reduced production of NADPH, and in turn glutathione (GSH) levels. TIGAR protects against oxidative stress-induced apoptosis. The suppression of TIGAR and NADPH levels thus contributed to ROS-mediated late apoptosis/necrosis of multiple myeloma cells. These findings indicate that multiple myeloma cells are dependent on MUC1-C and TIGAR for maintenance of redox balance and that targeting MUC1-C activates a cascade involving TIGAR suppression that contributes to multiple myeloma cell death.Blood 11/2011; 119(3):810-6. · 9.06 Impact Factor
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ABSTRACT: Erlotinib and pemetrexed have been approved for the second-line treatment of non-small cell lung cancer (NSCLC). These two agents have different mechanisms of action. Combined treatment with erlotinib and pemetrexed could potentially augment the antitumor activity of either agent alone. In the present study, we investigated the safety profile of combined administration of the two agents in pretreated NSCLC patients. A phase I dose-finding study (Trial registration: UMIN000002900) was performed in patients with stage III/IV nonsquamous NSCLC whose disease had progressed on or after receiving first-line chemotherapy. Patients received 500 mg/m2 of pemetrexed intravenously every 21 days and erlotinib (100 mg at Level 1 and 150 mg at Level 2) orally on days 2-16. Twelve patients, nine males and three females, were recruited. Patient characteristics included a median age of 66 years (range, 48-78 years), stage IV disease (nine cases), adenocarcinoma (seven cases) and activating mutation-positives in the epidermal growth factor receptor gene (two cases). Treatment was well-tolerated, and the recommended dose of erlotinib was fixed at 150 mg. Dose-limiting toxicities were experienced in three patients and included: grade 3 elevation of serum alanine aminotransferase, repetitive grade 4 neutropenia that required reduction of the second dose of pemetrexed and grade 3 diarrhea. No patient experienced drug-induced interstitial lung disease. Three patients achieved a partial response and stable disease was maintained in five patients. Combination chemotherapy of intermittent erlotinib with pemetrexed was well-tolerated, with promising efficacy against pretreated advanced nonsquamous NSCLC.BMC Cancer 07/2012; 12:296. · 3.33 Impact Factor
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ABSTRACT: Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been shown to have benefits for non-small cell lung cancer and pancreatic cancer patients; however, almost all patients develop progressive disease during the therapy. On the other hand, it has been reported that a tumor continues to express epidermal growth factor receptor even after developing progressive disease. To demonstrate the clinical relevance of erlotinib treatment after progressive disease, we investigated whether continuous administration of erlotinib in combination with chemotherapy has a useful effect on progressive disease development during erlotinib treatment. For this purpose, we examined the antitumor effect of a combination therapy of a chemotherapeutic agent with erlotinib using two types of erlotinib-resistant tumor xenograft models: a non-small cell lung cancer model, in which EBC-1, H1975 and HCC827TR3 tumors were implanted, and an HPAC pancreatic cancer cell xenograft which generates erlotinib-resistant tumors in vivo. As a result, the combination therapy showed a significantly higher antitumor activity compared with chemomonotherapy in all xenograft models except the H1975 xenografts. Furthermore, erlotinib alone suppressed the phosphorylation of epidermal growth factor receptor in HPAC tumors and the two non-small cell lung cancer cell lines other than H1975. Therefore, combination therapy which uses erlotinib can be considered effective if epidermal growth factor receptor phosphorylation is inhibited by erlotinib, even in erlotinib-resistant tumor xenograft models. Our results suggest that the continuous inhibition of epidermal growth factor receptor phosphorylation by erlotinib after progressive disease enhances the antitumor activity of chemotherapy.Oncology Reports 12/2011; 27(4):923-8. · 2.30 Impact Factor