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1.  Combined cetuximab and trastuzumab are superior to gemcitabine in the treatment of human pancreatic carcinoma xenografts 
Annals of Oncology  2009;21(1):98-103.
Pancreatic carcinoma remains a treatment-refractory cancer with a poor prognosis. Here, we compared anti-EGF receptor and anti-HER2 monoclonal antibodies (2mAbs) injections with standard gemcitabine treatment on human pancreatic carcinoma xenografts.
Materials and Methods
Nude mice, bearing human pancreatic carcinoma, xenografts, were treated with either combined anti-EGFR (cetuximab) and anti-HER2 (trastuzumab), or gemcitabine and tumor growth were observed.
Results and Conclusion
In first-line therapy, mice survival was significantly longer in 2mAbs groups compared to gemcitabine (p<0.0001: BxPC-3; p=0.0679: MiaPaCa-2; p=0.0019: Capan-1) and to controls (p<0.0001). In second-line therapy tumor regressions were observed after replacing gemcitabine by 2mAbs treatment, resulting in significantly longer animal survival, compared with mice receiving continuous gemcitabine injections (p=0.008, BxPC-3; p=0.05; MiaPaCa-2; p<0.001, Capan-1). Therapeutic benefit of 2mAbs was observed, despite K-Ras mutation. Interestingly, concerning the mechanism of action, coinjection of F(ab)′2 fragments from 2mAbs induced significant tumor growth inhibition, compared to controls (p=0.001), indicating that the 2mAbs had an, Fc-independent, direct action on tumor cells.
This pre-clinical study demonstrated a significant improvement of survival and tumour regression in mice treated with anti-EGFR/anti-HER2 2mAbs in first and second-line treatments, compared to gemcitabine, independently of the K-Ras status.
PMCID: PMC3508938  PMID: 19889608
Animals; Antibodies, Monoclonal; administration & dosage; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; therapeutic use; Blotting, Western; Cell Line, Tumor; Deoxycytidine; analogs & derivatives; therapeutic use; Female; Humans; Immunohistochemistry; Mice; Mice, Nude; Pancreatic Neoplasms; drug therapy; Receptor, Epidermal Growth Factor; antagonists & inhibitors; immunology; Receptor, erbB-2; antagonists & inhibitors; immunology; Xenograft Model Antitumor Assays; EGFR; gemcitabine; HER2; monoclonal antibodies; pancreatic carcinoma
2.  The epithelial-mesenchymal transition (EMT) phenomenon 
Annals of Oncology  2010;21 Suppl 7:vii89-vii92.
The epithelial-mesenchymal transition (EMT) describes a rapid and often reversible modulation of phenotype by epithelial cells. EMT was originally defined in the context of developmental stages, including heart morphogenesis, mesoderm and neural crest formation. Epithelial cells loosen cell-cell adhesion structures throughout EMT. They modulate their polarity, cytoskeleton organization and typically express vimentin filaments and downregulate cytokeratins. They become isolated, mobile and resistant to anoikis. The epithelial-mesenchymal transition at least superficially resembles the evolution from normal to transformed cell phenotype during carcinoma progression. The relevance of the concept of epithelial-mesenchymal transition in this context was suggested by in vitro models using transformed epithelial cells. Transduction pathways typical for embryogenic EMT in vivo were also found to be activated during cancer progression. More recently, it has been found that such pathways suggest an increased plasticity linked to cellular stemness and ability to generate tumors. However, in the absence of direct evidence, a number of oncologists and pathologists remain skeptical about applying the EMT concept to human tumor progression. In fact, EMT concept appears to be fully relevant in some situations, but the concept has to be adjusted in other situations to reflect tumor cell renewal and plasticity during carcinoma progression and metastasis.
PMCID: PMC3379967  PMID: 20943648
Animals; Cell Dedifferentiation; physiology; Epithelial-Mesenchymal Transition; physiology; Female; Humans; Mammary Neoplasms, Experimental; pathology; Mice; Neoplasms; etiology; pathology; Epithelium; differentiation; morphogenesis; invasiveness; apoptosis
3.  A phase I study of the safety and pharmacokinetics of trabectedin in combination with pegylated liposomal doxorubicin in patients with advanced malignancies 
Annals of Oncology  2008;19(10):1802-1809.
Background: To determine the maximum tolerated dose (MTD), safety, potential pharmacokinetic (PK) interactions, and effect on liver histology of trabectedin in combination with pegylated liposomal doxorubicin (PLD) for advanced malignancies.
Patients and methods: Entry criteria for the 36 patients included normal liver function, prior doxorubicin exposure <250 mg/m2, and normal cardiac function. A 1-h PLD (30 mg/m2) infusion was followed immediately by one of six trabectedin doses (0.4, 0.6, 0.75, 0.9, 1.1, and 1.3 mg/m2) infused over 3 h, repeated every 21 days until evidence of complete response (CR), disease progression, or unacceptable toxicity. Plasma samples were obtained to assess PK profiles.
Results: The MTD of trabectedin was 1.1 mg/m2. Drug-related grade 3 and 4 toxic effects were neutropenia (31%) and elevated transaminases (31%). Six patients responded (one CR, five partial responses), with an overall response rate of 16.7%, and 14 had stable disease (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) >4 months (39%). Neither drug had its PK affected significantly by concomitant administration compared with trabectedin and PLD each given as a single agent.
Conclusion: Trabectedin combined with PLD is generally well tolerated at therapeutic doses of both drugs in pretreated patients with diverse tumor types and appears to provide clinical benefit. These results support the need for additional studies of this combination in appropriate cancer types.
PMCID: PMC2598415  PMID: 18497430
ET-743; ovarian cancer; pegylated liposomal doxorubicin (PLD); sarcomas; trabectedin

Results 1-3 (3)