ABSTRACT
BACKGROUND: TNF-α has been proposed as a predictive factor for venous thromboembolism (VTE). Genetic polymorphisms could regulate TNF-α production. However, the relationship between TNFA gene variants and VTE is not clarified. This study aims to investigate the predictive role of five different TNFA gene promoter SNPs, or their haplotype combination(s), for a first VTE episode in gastrointestinal cancer out-patients treated with chemotherapy. PATIENTS AND METHODS: Serum TNF-α levels and TNFA -863C/A, -857C/T, -376G/A, -308G/A and -238G/A gene promoter polymorphisms were retrospectively evaluated in 314 subjects, including 157 controls and 157 Caucasian patients with histologically diagnosed GI cancers beginning chemotherapy delivery (5-fluorouracil either as monotherapy or in combination with platinum compounds or irinotecan). RESULTS: Haplotype analysis showed that a five-loci haplotype (CTGGG haplotype) has higher frequency in GI cancer patients who developed VTE (n = 15) during chemotherapy [odds ratio = 2.7, 95% confidence interval (CI) 1.04-7.11, P = 0.04]. GI patients who remained VTE-free did not differ in CTGGG haplotype frequency from controls. No association was observed between serum TNF-α levels and TNFA haplotype, but both were independent predictors of VTE. Approximately 20% of GI cancer patients carrying the CTGGG haplotype developed VTE compared with 4% of the remaining 101 patients (hazard ratio = 5.6, 95% CI 1.8-17.6, P = 0.003). CONCLUSION: These results suggest that TNFA might represent a candidate gene contributing to VTE pathogenesis in GI cancer patients and suggest that VTE risk during chemotherapy might be genetically identified. Validation studies are needed for translation into clinical practice.
Subject(s)
Gastrointestinal Neoplasms/drug therapy , Tumor Necrosis Factor-alpha/genetics , Venous Thromboembolism/chemically induced , Venous Thromboembolism/genetics , Adult , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/therapeutic use , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Agents, Phytogenic/therapeutic use , Camptothecin/adverse effects , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Case-Control Studies , Female , Fluorouracil/adverse effects , Fluorouracil/therapeutic use , Genetic Predisposition to Disease , Haplotypes/genetics , Humans , Irinotecan , Male , Middle Aged , Polymorphism, Single Nucleotide , Promoter Regions, Genetic/genetics , Retrospective Studies , Risk , Tumor Necrosis Factor-alpha/bloodSubject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Blood Coagulation Tests , Neoplasms/diagnosis , Thrombin/metabolism , Venous Thromboembolism/diagnosis , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Disease-Free Survival , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasms/complications , Neoplasms/drug therapy , Neoplasms/mortality , Neoplasms/physiopathology , Predictive Value of Tests , Protein C/metabolism , Sensitivity and Specificity , Venous Thromboembolism/etiology , Venous Thromboembolism/mortality , Venous Thromboembolism/physiopathology , Venous Thromboembolism/prevention & controlABSTRACT
An immortalized murine mesenchymal stem cell line (mTERT-MSC) enriched for Lin(neg)/Sca-1(pos) fraction has been obtained through the transfection of MSC with murine TERT and single-cell isolation. Such cell line maintained the typical MSC self-renewal capacity and continuously expressed MSC phenotype. Moreover, mTERT-MSC retained the functional features of freshly isolated MSC in culture without evidence of senescence or spontaneous differentiation events. Thus, mTERT-MSC have been cultured onto PLA films, 30 and 100 microm PLA microbeads, and onto unpressed and pressed HYAFF-11 scaffolds. While the cells adhered preserving their morphology on PLA films, clusters of mTERT-MSC were detected on PLA beads and unpressed fibrous scaffolds. Finally, mTERT-MSC were not able to colonize the inner layers of pressed HYAFF-11. Nevertheless, such cell line displayed the ability to preserve Sca-1 expression and to retain multilineage potential when appropriately stimulated on all the scaffolds tested.
Subject(s)
Antigens, Ly/metabolism , Biocompatible Materials/chemistry , Biocompatible Materials/metabolism , Membrane Proteins/metabolism , Mesenchymal Stem Cells/metabolism , Tissue Scaffolds/chemistry , Animals , Apoptosis/drug effects , Cell Differentiation/drug effects , Cell Line, Transformed , Cell Lineage/drug effects , Cell Shape/drug effects , Cytoprotection/drug effects , Hydrogen Peroxide/pharmacology , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/drug effects , Mice , Oxidative Stress/drug effects , Phenotype , Polymers/chemistry , Telomerase/metabolism , Transduction, GeneticABSTRACT
Fotemustine is a cytotoxic alkylating agent, belonging to the group of nitrosourea family. Its mechanism of action is similar to that of other nitrosoureas, characterized by a mono-functional/bi-functional alkylating activity. Worth of consideration is the finding that the presence of high levels of the DNA repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT) in cancer cells confers drug resistance. In different clinical trials Fotemustine showed a remarkable antitumor activity as single agent, and in association with other antineoplastic compounds or treatment modalities. Moreover, its toxicity is generally considered acceptable. The drug has been employed in the treatment of metastatic melanoma, and, on the basis of its pharmacokinetic properties, in brain tumors, either primitive or metastatic. Moreover, Fotemustine shows pharmacodynamic properties similar to those of mono-functional alkylating compounds (e.g. DNA methylating drugs, such as Temozolomide), that have been recently considered for the management of acute refractory leukaemia. Therefore, it is reasonable to assume that this agent could be a good candidate to play a potential role in haematological malignancies.
