ABSTRACT
BACKGROUND: Increasing evidence suggests that a pro-inflammatory microenvironment affects distant metastasis of breast cancer cells, in particular by favoring tumor cell adhesion to endothelium. The aim of this study was to investigate the potential of different anti-inflammatory drugs to inhibit this effect in vitro. MATERIALS AND METHODS: Breast cancer cells from the metastatic cell line KM22 were incubated with activated Human umbilical vein endothelial cells (HUVECs). Tumor cell adhesion was quantified by fluorescence microscopy. The anti-inflammatory drugs ibuprofen, aspirin (acetylsalicylic acid), diclofenac, and dexamethasone were used as inhibiting agents. RESULTS: Aspirin and dexamethasone significantly reduced breast cancer cell adhesion to HUVECs (20.3%, p<0.000; and 25%, p<0.05, respectively). Ibuprofen and diclofenac did not significantly reduce tumor cell adhesion. CONCLUSION: Aspirin and dexamethasone seem to be able to partly inhibit adhesion of breast cancer cells to endothelium. Future studies should attempt to optimize this effect in vitro, in preparation for potential in vivo trials.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Breast Neoplasms/pathology , Cell Adhesion/drug effects , Endothelium, Vascular/drug effects , Cell Line, Tumor , Endothelium, Vascular/pathology , Female , Humans , In Vitro Techniques , Microscopy, FluorescenceABSTRACT
Vascular endothelial growth factor seems to be a promoter of tumor progression for epithelial ovarian cancer. New drugs such as bevacizumab, either alone or in combination with metronomic chemotherapy, suppress tumor growth and have proved to be effective in various tumor types. We present a 60-year-old patient with heavily pretreated, recurrent epithelial ovarian cancer, who received bevacizumab (10 mg/m(2)) every 2 weeks in combination with metronomic administered low-dose cyclophosphamide (50 mg/day orally) after failing four explorative laparotomies and multiple chemotherapy regimes. At the time of writing, February 2011, she was being treated with this combination therapy for 24 months and the progression-free survival still continues. Treatment of advanced, refractory epithelial ovarian cancer with bevacizumab in combination with low-dose cyclophosphamide could be a very effective salvage treatment option in heavily pretreated patients.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclophosphamide/administration & dosage , Neoplasms, Glandular and Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Administration, Metronomic , Bevacizumab , Carcinoma, Ovarian Epithelial , Disease-Free Survival , Female , Humans , Middle AgedABSTRACT
BACKGROUND: Liver metastasis is associated with a proinflammatory microenvironment and up-regulation of cell adhesion molecules expressed by endothelial cells. The aim of this study was to characterize the interrelations between breast cancer cell-secreted cytokines, macrophages and E-selectin-mediated cancer cell adhesion and their role in metastasis of breast cancer. MATERIALS AND METHODS: Three metastatic breast cancer cell lines (1590, KM22, ZE) were studied. Cell culture supernatants were screened for cytokines and the potential for cytokines to increase tumor-necrosis factor-α (TNF-α) production by ANA-1-macrophages was analyzed. E-Selectin-mediated tumor cell adhesion of fluorescence labelled tumor cells was evaluated by measurement of fluorescence intensity with and without E-selectin-blocking strategies (monoclonal antibodies, cimetidine). RESULTS: Tumor-specific cytokine secretion patterns were revealed. TNF-α secretion from cultured macrophages increased after incubation with tumor supernatants. Tumor cell adhesion was significantly inhibited by cimetidine and monoclonal antibodies against E-selectin (KM22 with cimetidine, p<0.05). CONCLUSION: Breast cancer cell-secreted cytokines stimulate macrophages to produce TNF-α, a known up-regulator of E-selectin expression, and therefore cell adherence to endothelium. Inhibition of this mechanism could be an attractive therapeutic option for the prevention of breast cnacer metastasis.
Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cytokines/metabolism , Macrophages/pathology , Neoplasm Metastasis/pathology , Animals , Antibodies, Monoclonal/pharmacology , Cell Adhesion/drug effects , Cell Line, Tumor , Cimetidine/pharmacology , E-Selectin/immunology , Endothelial Cells/cytology , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Female , Humans , Macrophages/drug effects , Macrophages/metabolism , Mice , Solubility/drug effects , Subcellular Fractions/drug effects , Subcellular Fractions/metabolism , Tumor Necrosis Factor-alpha/biosynthesis , Umbilical Veins/cytology , Up-Regulation/drug effectsABSTRACT
BACKGROUND: The prognosis of patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC) is poor. There is no standard treatment available. Emerging evidence suggests a major role for antiangiogenic treatment modalities in EOC, in particular in combination with the metronomic application of low dose chemotherapy. The novel, investigational oral antiangiogenic agent pazopanib targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and c-kit is currently being studied in different tumour types and is already used as first line therapy in recurrent renal cell carcinoma. A combined therapy consisting of pazopanib and metronomic oral cyclophosphamide may offer a well-tolerable treatment option to patients with recurrent, pretreated EOC. METHODS/DESIGN: This study is designed as a multicenter phase I/II trial evaluating the optimal dose for pazopanib (phase I) as well as activity and tolerability of a combination regimen consisting of pazopanib and metronomic cyclophosphamide in the palliative treatment of patients with recurrent, platinum-resistant, pre-treated ovarian cancer (phase II). The patient population includes patients with histologically or cytologically confirmed diagnosis of EOC, cancer of the fallopian tube or peritoneal cancer which is platinumresistant or -refractory. Patients must have measurable disease according to RECIST criteria and must have failed available standard chemotherapy. Primary objectives are determination of the optimal doses for pazopanib (phase I) and the overall response rate according to RECIST criteria (phase II). Secondary objectives are time to progression, overall survival, safety and tolerability. The treatment duration is until disease progression or intolerability of study drug regimen (with a maximum of 13 cycles up to 52 weeks per subject). DISCUSSION: The current phase I/II trial shall clarify the potential of the multitargeting antiangiogenic tyrosinkinaseinhibitor GW 786034 (pazopanib) in combination with oral cyclophosphamide as salvage treatment in patients with recurrent, pretreated ovarian cancer.
