Novel trastuzumab-DM1 conjugate: Synthesis and bio-evaluation

Antibody-drug conjugates are now of considerable interest and are recommended for the treatment of cancers. Linkers are having a crucial role in potency and efficacy of these drugs. Herein, for the first time, we have used a water-soluble poly-ethylene glycol based linker (succinimidyl-[(N-maleimido propionamido)-diethyleneglycol] [SM(PEG)2]) for lysine amide coupling of DM1 drug to trastuzumab considering evaluation of the effect of using a hydrophilic linker on physicochemical and biological properties of the resulting conjugate in comparison to the conjugate containing succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) linker, which has a relative hydrophobic nature. The physicochemical properties of synthesized conjugates were investigated in terms of drug to antibody ratio, size variants and free drug quantities. In vitro biological activity of trastuzumab-DM1 conjugates was assessed on breast cancer cell lines expressing different levels of HER2 using binding affinity, antiproliferative, apoptosis, and antibody-dependent cell-mediated cytotoxicity (ADCC) assays. Synthesized conjugate containing hydrophilic linker, showed higher drug to antibody ratio, no aggregated form and higher cellular toxicity in comparison to SMCC bearing conjugate. Binding affinity and ADCC potential of conjugates was not affected upon the usage of hydrophilic linker. In conclusion, application of SM(PEG)2 for coupling of DM1 to trastuzumab enhance desirable characteristics of the resulting conjugate.     

Association of xenobiotic-metabolizing enzymes (GSTM1 and GSTT 1), and pro-inflammatory cytokines (TNF-α and IL-6) genetic polymorphisms with non-alcoholic fatty liver disease

Molecular Biology Reports - Previous studies have revealed that genetic polymorphisms of the Glutathione S-transferase M1 and T1 (GSTM1 and GSTT1), tumor necrosis factor-α (TNF-α), and...     

Identification of two major direct repeat unit clusters, 8i and 11ce,among methicillin resistant Staphylococcus aureus strains: the emergence of novel dru types and repeats

Molecular Biology Reports - The changing epidemiology and decreasing susceptibility to first-line antibiotics, such as vancomycin and linezolid, leave clinicians with few therapeutic options for...     

A review of drug therapy for sporadic fatal insomnia

Background: Sporadic fatal insomnia (sFI) is a rapid progressive neurodegenerative disease characterised by gradual to perpetual insomnia, followed by dysautonomia, coma and death.¹ Lugaresi E, Medori R, Montagna P, Baruzzi A, Cortelli P, Lugaresi A, Tinuper P, Zucconi M, Gambetti P. Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. New England J of Med. 1986;315:997–1003. doi:10.1056/NEJM198610163151605.[Crossref], [PubMed], [Web of Science ®] [Google Scholar] The cause of sFI was recently mapped to a mutation in a protein, the prion, found in the human brain. It is the unfolding of the prion that leads to the generation of toxic oligomers that destroy brain tissue and function. Recent studies have confirmed that a methionine mutation at codon 129 of the human Prion is characteristic of sFI. Current treatment slows down the progression of the disease, but no cure has been found, yet. Methods: We used Molecular Docking and Molecular Dynamics simulation methods, to study the toxic Fatal-Insomnia-prion conformations at local unfolding. The idea was to determine these sites and to stabilise these regions against unfolding and miss-folding, using a small ligand, based on a phenothiazine "moiety". Conclusion: As a result we here discuss current fatal insomnia therapy and present seven novel possible compounds for in vitro and in vivo screening.     

Association of a Genetic Variant in the Cyclin-Dependent Kinase Inhibitor 2B with Risk of Pancreatic Cancer

Background:Pancreatic cancer (PC) is among the most aggressive tumors with a poor prognosis, indicating the need for the identification of a novel prognostic biomarker for risk stratifications. Recent genome-wide association studies have demonstrated common genetic variants in a region on chromosome 9p21 associated with an increased risk of different malignancies.Methods:In the present study, we explore the possible relationship between genetic variant, rs10811661, and gene expression of CDKN2B in 75 pancreatic cancer patients, and 188 healthy individuals. DNAs were extracted and genotyping and gene expression were performed by TaqMan real-time PCR and RT-PCR, respectively. Logistic regression was used to assess the association between risk and genotypes, while the significant prognostic variables in the univariate analysis were included in multivariate analyses.Results:The patients with PDAC had a higher frequency of a TT genotype for rs10811661 than the control group. Also, PDAC patients with dominant genetic model, (TT + TC), was associated with increased risk of developing PDAC (OR= 14.71, 95% CI [1.96-110.35], p= 0.009). Moreover, patients with CC genotype had a higher expression of CDKN2B, in comparison with TT genotype.Conclusion:Our findings demonstrated that CDKN2A/B was associated with the risk of developing PDAC, supporting further investigations in the larger and multicenter setting to validate the potential value of this gene as an emerging marker for PDAC. Key Words: CDKN2A/B, Rs10811661, Pancreatic cancer, Prognostic biomarker