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Purpose: When during cancer treatment resistance to a tyrosine kinase inhibitor (TKI) occurs, switching to another TKI is often considered as a reasonable option. Previously, we reported that resistance to sunitinib may be caused by increased lysosomal sequestration, leading to increased intracellular lysosomal storage and, thereby, inactivity. Here, we studied the effect of several other TKIs on the development of (cross-) resistance. Methods: TKI resistance was induced by continuous exposure of cancer cell lines to increasing TKI concentrations for 3-4 months. (Cross-) resistance was evaluated using MTT cell proliferation assays. Intracellular TKI concentrations were measured using LC-MS/MS. Western blotting was used to detect lysosome-associated membrane protein-1 and −2 (LAMP1/2) expression. Results: The previously generated sunitinib-resistant (SUN) renal cancer cells (786-O) and colorectal cancer cells (HT-29) were found to be cross-resistant to pazopanib, erlotinib and lapatinib, but not sorafenib. Exposure of 786-O and HT-29 cells to sorafenib, pazopanib or erlotinib for 3-4 months induced drug resistance to pazopanib and erlotinib, but not sorafenib. Intracellular drug accumulation was found to be increased in pazopanib- and erlotinib-, but not in sorafenib-exposed cells. Lysosomal capacity, reflected by LAMP1/2 expression, was found to be increased in resistant cells and, in addition, to be transient. No cross-resistance to the mTOR inhibitor everolimus was detected. Conclusions: Our data indicate that tumor cells can develop (cross-) resistance to TKIs, and that such resistance includes increased intracellular drug accumulation accompanied by increased lysosomal storage. Transient (cross-) resistance was found to occur for several of the TKIs tested, but not for everolimus, indicating that switching from a TKI to a mTOR inhibitor may be an attractive therapeutic option. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to determine the maximum-tolerated doses (MTDs) and the dose-limiting toxicities of a metronomic administration of oral vinorelbine and cisplatin in patients with advanced/metastatic NSCLC. Twenty-six patients with advanced/metastatic NSCLC were enrolled. Escalating doses of vinorelbine (40-70 mg p.o./trice per week) and cisplatin (70-85 mg/m intravenous infusion) were administered on day 1 every 3 weeks. ΜΤDs were reached at 60 mg thrice/week p.o. for vinorelbine and 85 mg/m for cisplatin. Grade 4 neutropenia, febrile neutropenia and grade 4 diarrhea were the dose-limiting events during the first cycle of chemotherapy. The most common grade III-IV hematologic toxicity was neutropenia occurring in seven (27%) patients, while non-hematological toxicities were relatively infrequent and mostly of grade I or II. Objective responses were observed in 20.8% of patients with measurable disease. The regimen of metronomic administration and cisplatin is feasible and active in patients with NSCLC. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the efficacy and toxicity of the docetaxel and capecitabine combination in patients with previously treated, unresectable adenocarcinoma of the pancreas. Patients and Methods: Patients with pancreatic adenocarcinoma, pre-treated with gemcitabine-based chemotherapy, were treated with capecitabine (800 mg/m orally, twice a day for 14 days) and docetaxel (75 mg/m i.v, on day1), every 3 weeks. The primary end-point was overall response rate (RR). Results: Thirty-one patients were enrolled in the study; 93.6% of them had a performance status (PS) of 0-1 and 96.8% had stage IV disease. Patients received a median of 4 cycles/patient, and the main reason for treatment discontinuation was disease progression. Partial response was observed in three (9.7%) patients, stable disease in seven (22.6%) (disease control rate: 32.3%, 95% CI: 15.80-48.71%) and disease progression in 21 (67.6%). The median progression-free survival (PFS) was 2.4 months (95% CI: 1.6-3.13) and the median overall survival (OS) was 6.3 months (95% CI: 3.38-9.23); the estimated 1-year survival rate was 14.7%. Grade III/IV neutropenia occurred in 10 (32.2%) patients and febrile neutropenia in one patient. Other severe non-hematologic toxicities were mild and manageable. After 2 chemotherapy cycles, pain control occurred in 20% of patients and stabilization of body weight in 40%. Conclusion: The combination of docetaxel/capecitabine may confer good disease control associated with improvement of quality of life as second-line chemotherapy in patients with metastatic pancreatic cancer. [ABSTRACT FROM AUTHOR]

The aim of the present study was to develop chick-embryo chorioallantoic membrane (CAM) bioluminescent tumor models employing low passage cell cultures obtained from primary pancreatic ductal adenocarcinoma (PDAC) cells. Primary PDAC cells transduced with lentivirus expressing Firefly-luciferase (Fluc) were established and inoculated onto the CAM membrane, with >80% engraftment. Fluc signal reliably correlated with tumor growth. Tumor features were evaluated by immunohistochemistry and genetic analyses, including analysis of mutations and mRNA expression of PDAC pivotal genes, as well as microRNA (miRNA) profiling. These studies showed that CAM tumors had histopathological and genetic characteristic comparable to the original tumors. We subsequently tested the modulation of key miRNAs and the activity of gemcitabine and crizotinib on CAM tumors, showing that combination treatment resulted in 63% inhibition of tumor growth as compared to control (p < 0.01). These results were associated with reduced expression of miR-21 and increased expression of miR-155. Our study provides the first evidence that transduced primary PDAC cells can form tumors on the CAM, retaining several histopathological and (epi)genetic characteristics of original tumors. Moreover, our results support the use of these models for drug testing, providing insights on molecular mechanisms underlying antitumor activity of new drugs/combinations. [ABSTRACT FROM AUTHOR]