| dc.description.abstract | Breast cancer is the second most prevalent cancer in women worldwide. It is treated by various strategies, including surgery, radiation therapy, hormonal therapy, targeted therapy and chemotherapy. Chemotherapeutic drugs like cyclophosphamide, doxorubicin, paclitaxel and docetaxal are used to treat the cancer either alone or in combination with other therapies, such as surgery, radiation, or hormone therapy depending upon the stage and the location of cancer cells. Cyclophosphamide and doxorubicin are also given in combination known as adjuvant chemotherapy (AC therapy). However, all the patients do not get benefited by this treatment. Inter-individual response in patients on AC therapy might be on account of variation in genes involved in pharmacokinetics and pharmacodynamics of cyclophosphamide and doxorubicin. Therefore, a detailed pharmacogenomic study was performed using global screening array microchip that contains more than 700,000 upto-date markers, optimized for human genome-wide backbone for unparalleled genomic coverage, including clinically relevant content and all pharma GKB markers. Two gene variants CYP2C19*2 and ALDH1A1*2 involved in the metabolism of cyclophosphamide were found to influence the clinical outcome in breast cancer patients on AC therapy in Malwa region of Punjab. However, none of the gene variants involved in pharmacokinetics vi and pharmacodynamics of doxorubicin were found to be involved in the interindividual response. Therefore, patients should be screened for CYP2C19*2 and ALDH1A1*2 gene variants before prescribing the AC therapy. Due to several problems with the chemotherapeutic drugs the new therapeutic strategies have been introduced in the recent past that have led to the target based drug design. In an attempt to develop new drugs for targeting breast cancer, imidazole based anti-cancer agents were computationally designed and synthesized (Series 1 and Series 2). All the compounds were first assessed for their anti-proliferative activity in T47D, MDA-MB-231, and MCF7 breast cancer cell lines. Lead compounds with IC50 values less than 10 µM in at least two cell lines such as A12, SA1, SA3, SA8, SA11 from series 1 and SRA1, SRA8, SRA12, SRA14 from series 2 were selected for further evaluation of their cytotoxicity (if any) against normal HBL100 and HPBMC cell lines. Two compounds SRA12 and SRA14 were found to be non toxic and upon lead optimisation through in silico approach at CDK4/6 protein afforded ANP12 that emerged out to be potent anticancer compound and exhibited good anti- breast cancer profile. Compounds ANP12 and SRA14 (from series 2) elevated ROS levels, altered mitochondrial membrane potential and induced cell cycle arrest at G0 phase indicating their anticancer mechanism possibly via CDK4/6 inhibiton. | en_US |
