Razi Journal of Medical Sciences

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Background: Immunotoxins, one of the promising therapeutic agents can be used in targeted of cancer therapy based on specific binding to tumor-related antigen. Evaluating and specifying the structural and functional features of these antigens provide new perspectives in the field of cancer therapy. In this study, we decipher the structure and function of MAGE antigen family based on in-silico and bioinformatic evaluation.
Methods: In the first step, using SPSS software statistical analysis of the MAGE family antigens expression in a variety of cancer types was performed. After determining the MAGE- A4 as a superior antigen with the highest expression level, based on the review of the literature, the MAGE-A4 binding epitopes were identified for HLA isoforms. Then bioinformatic databases such as BIMAS and SYFPEITHI programs were used to confirm the reported HLA-binding epitopes in literature. Stability index and immunogenicity of epitopes were defined by ProtPram and IEDB software respectively. To determine the binding affinity and stability of HLA-peptide complex, docking screening and molecular dynamic simulation was conducted using Autodock Vina and gromacs 5.1 softwares.
Results: Our results revealed that the MAGE-A4 antigen had high expression compared with other MAGE family members. Also, MAGE-A4 derived peptide, VDELAHFLL, with the highest stability and favorable immunogenicity was appeared. On the other hand, the most stable of HLA-B37- VDELAHFLL complex with the lowest amount of RMSD plot was Obtained.
Conclusion: Generally, our results indicated that VDELAHFLL desired peptide from MAGE-A4 antigen might be promising to generate the therapeutic monoclonal antibody and vaccine development in modern cancer therapy.

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Background: The androgen receptor belongs to the family of transcription factors of the steroid hormones receptor, and according to studies, single nucleotide mutations in the structure of this protein can affect its function and response to inhibitory drugs. In regard this purpose of this study was to investigate the effect of the single-nucleotide polymorphism rs137852585 presence in the androgen receptor-encoding gene on the response of this form to treatment with enzalutamide and to study its frequency in Iranian population.
 Methods: In this case-control study, 10 ml peripheral blood was taken from 50 prostate cancer patients and 50 healthy people. Then the genomic DNA of the samples was extracted and isolated. ARMS-PCR and direct sequencing were used to determine the presence of polymorphism and the data were analyzed using SISA statistical database and Fisher's exact test. On the other hand, to evaluate the effect of mutation on the function of the androgen receptor, the Docking technique and the Autodock 4.2 software were used. Finally, determination of the allele frequency, heterozygosity and the investigation of the existence of Hardy-Weinberg equilibrium were performed using the Genepop computational server.
Results: Investigations showed that the allele frequency for rs137852585 increased for mutated allele in patients with prostate cancer (0.24) compared to healthy subjects (0.08) (p=0.003). On the other hand, reviewing the results of Docking showed that mutation in the androgen receptor structure makes enzalutamide-androgen receptor interactions thermodynamically undesirable. Demographic analyzes showed that this marker is at the Hardy-Weinberg equilibrium in the Iranian population (p>0.05).
Conclusion: The presence of single nucleotide polymorphisms induces resistance to enzalutamide by altering the active site of the androgen receptor. On the other hand, the presence of mutant allele of rs137852585 could increase prostate cancer risk.