The role of calcium in paracetamol (acetaminophen) cytotoxicity in PC12 cells transfected with CYP4502E1.

Paracetamol-induced toxicity is mainly due to the accumulation of its CYP450-mediated N-hydroxylation product - N-acetylimidoquinone. We examined cell viability, proliferation rates and intracellular calcium in PC12 cells and in a PC12 cell line transfected with cytochrome P4502E1 exposed to paracetamol. This drug had a concentration-related effect on cell survival and a LD(50) which was significantly different between both cell types.

A phase I study of the optimized cryptic peptide TERT(572y) in patients with advanced malignancies.

Objective: It was the aim of this study to evaluate the safety of the optimized cryptic peptide TERT(572Y) in pretreated patients with advanced cancer.

Methods: Nineteen patients with progressive and chemotherapy-refractory tumors received escalated doses (2-6 mg) of 2 subcutaneous injections of the optimized TERT(572Y) peptide followed by 4 subcutaneous injections of the native TERT(572) peptide every 3 weeks. Both TERT peptides were coinjected with adjuvant Montanide ISA51.

Optimal organization of a polypeptide-based candidate cancer vaccine composed of cryptic tumor peptides with enhanced immunogenicity.

Polyspecific tumor vaccination should offer broad control of tumor cells and reduce the risk of emergence of immune escape variants. Here, we evaluated the capacity of a polypeptide composed of optimized cryptic peptides derived from three different universal tumor antigens (TERT988Y, HER-2/neu402Y and MAGE-A248V9) to induce a polyspecific CD8 cell response both in vivo in HHD mice and in vitro in humans. A mixture of TERT988Y, HER-2/neu402Y and MAGE-A248V9 peptides failed to induce a trispecific response.

A three-dimensional tumor cell defect in activating autologous CTLs is associated with inefficient antigen presentation correlated with heat shock protein-70 down-regulation.

We described previously a CTL clone able to lyse the autologous carcinoma cell line IGR-Heu after specific recognition of an HLA-A2/mutated alpha-actinin-4 peptide complex. Here, we used IGR-Heu, cultured either as standard two-dimensional monolayers or as three-dimensional spheroids, to further analyze the influence of target architecture on CTL reactivity. Interestingly, we found that changes in the tumor structure from two- to three-dimensional induced a dramatic decrease in its capacity to activate autologous CTL, as measured by IFN-gamma and tumor necrosis factor-alpha secretion.