ABSTRACT
Mesalamine (5-ASA) is one of the drugs indicated as first line therapy in ulcerative colitis for induction and maintenance of remission. Sulfasalazine and formulations of 5-ASA (pH-dependent and controlled release formulations) were developed to minimize the systemic absorption and maximize the delivery of the mesalamine to colon. Although, its efficacy and safety is well documented there are approximately 30% nonresponders to 5-ASA therapy. This necessitates the need for novel therapeutic options to improve the efficacy and safety of the currently available 5-ASA therapy. CLX-103 is a novel, patented prodrug molecular conjugate of mesalamine, eicosapentaenoic acid and caprylic acid designed to offer incremental benefits over the currently approved 5-ASA formulations. Results of in vitro and in vivo studies showed that CLX-103, was stable in simulated gastric fluid, but undergoes enzymatic hydrolysis in the small/large intestines to release the active moiety. Our data also showed that the active moiety is retained in the targeted intestinal tissues (ileum and colon) over a longer period of time in relation to sulfasalazine. The in vitro data supports the observed in vivo plasma kinetics of 5-ASA characterized by longer Tmax, low Cmax after the oral administration of CLX-103. Efficacy study of CLX-103 in acute dextran sodium sulfate (DSS) mouse colitis model showed improved potency measured as Disease Activity Index (DAI) and histological scores in the colon as compared to sulfasalazine. These findings indicate that CLX-103 could offer a differentiated drug product which is more efficacious and safer than the currently approved 5-ASA formulations in the treatment of inflammatory bowel diseases.
Subject(s)
Aminosalicylic Acids/therapeutic use , Caprylates/therapeutic use , Colitis/drug therapy , Colon/drug effects , Eicosapentaenoic Acid/analogs & derivatives , Eicosapentaenoic Acid/therapeutic use , Inflammatory Bowel Diseases/drug therapy , Prodrugs/therapeutic use , Animals , Caprylates/chemical synthesis , Colitis/chemically induced , Colon/metabolism , Colon/pathology , Dextran Sulfate , Drug Discovery , Drug Evaluation, Preclinical , Eicosapentaenoic Acid/chemical synthesis , Humans , Male , Mesalamine/chemistry , Mesalamine/therapeutic use , Mice , Mice, Inbred C57BL , Rats , Rats, Sprague-Dawley , Sulfasalazine/therapeutic useABSTRACT
BACKGROUND: The phosphatidylinositol 3-kinase (PI3K) pathway plays a significant role in apoptosis, cellular proliferation and motility. The aim of the present study was to analyze mutations and gene expression profiles of the PI3KCA gene to determine any role in breast carcinomas. MATERIALS AND METHODS: We analyzed 38 breast cancers for mutations in the two PIK3CA hotspots in exons 9 and 20 by direct sequencing of DNA obtained from biopsy samples. We have also analyzed expression of the PI3KCA gene in 38 breast carcinoma tumor and corresponding control tissue samples at the mRNA level by RT-PCR. The Fisher's exact test (2?2 only) was performed using MedCalc software for to examine associations with mRNA levels. RESULTS: In the present study a total of 13 cases demonstrated somatic mutations. In 9/13 cases 1633 G>A (E545K) were found in exon 9, whereas in exon 20, 4/13 cases had 3140A>G mutation. Our combined analysis showed PI3KCA mutations present in 34% of human breast cancer patients. In our study, we have also clearly found significantly higher expression in breast cancer tissues in comparison with control tissues (p=0.001). CONCLUSIONS: PIK3CA mutation is an emerging tumor marker that, in the future, might be used in the process of choosing a treatment. The detection of PI3KCA mutation might have important clinical implications for diagnosis, progression and therapy.
Subject(s)
Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Carcinoma, Ductal, Breast/genetics , Gene Expression Regulation, Neoplastic , Mutation , Phosphatidylinositol 3-Kinases/genetics , RNA, Messenger/genetics , Adult , Aged , Breast Neoplasms/metabolism , Carcinoma, Ductal, Breast/metabolism , Class I Phosphatidylinositol 3-Kinases , Exons/genetics , Female , Humans , Middle Aged , Phosphatidylinositol 3-Kinases/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis, DNAABSTRACT
Tripple negative breast cancer (TNBC) accounts for approximately 15% of breast cancers. It is defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and HER-2 Over expression. Expression of ER, PR and HER-2 plays an important role in therapeutic assessment of patients with breast cancer. TNBC is not one disease, but a family of diseases, some of which are highly aggressive with limited treatment options. Triple-negative breast cancers Patients are not benefiting from currently available receptor-targeted systemic therapy. At present, there is no single agent that targets triple-negative breast cancer. However, researchers are presently investigating large number of potential therapies that may eventually improve outcomes in these patients. In this review article, we discussed about tripple negative breast cancer, also the role of BRCA gene mutations and targeted therapeutic options available to triple negative breast cancer patients.