The long-term goal of this proposal is to develop more effective therapies for cancer, specifically pancreatic cancer. The specific focus of this proposal is to improve upon the anti-cancer activity of the drug gemcytabine. This will be accomplished by synthesizing novel conjugates of gemcytabine in a form that enables increased pathways for uptake into cancer cells and additional paths to rapid activation once inside cells. Gemcytabine requires activation within a cell before it can demonstrate its anti-cancer activity. The novel compounds will incorporate a form of gemcytabine already preactivated. The specific aims of this project are: (1) To synthesize 5 novel gemcytabine based compounds and assess their stability in plasma and laboratory conditions; and (2), complete characterization of these novel compound's activities in a number of cancer cell lines. This will include quantitation of the compounds effects on cell killing, colony formation ability and cell migration ability. In addition we will quantitate the rate of formation of the most active forms of gemcytabine found within the cells at various times after exposure to the drug and novel compounds. To investigate the mechanism of cellular uptake, activity and bioanalytical endpoints will be assessed in the presence and absence of inhibitors of the standard nucleoside transporters used by Gem. Positive results from this proposed research will provide multiple assets to MBC Pharma's commercialization efforts. A new lead compound for treating pancreatic cancer will provide assets for licensing. In addition, the demonstration of a lead compound from novel drug platform will enable the potential development of multiple compounds for different indications. It is anticipated that this technology will ultimately result in therapeutic agents that will significanty improve the outcomes of cancer patients.
Public Health Relevance Statement: Public Health Relevance: Ductal adenocarcinoma of the pancreas is one of the most intractable of human malignancies. It causes approximately 33,000 deaths in the United States every year, with an overall median 5-year survival rate of less than 5%. Effective systemic therapies are lacking, due in part to the intrinsic drug resistance of pancreatic cancer. The goal of this project is to use non-toxic vitamin B6 derivatization of gemcitabine to provide preactivated prodrug inside the cells. This drug design has the potential to greatly improve the properties of gemcitabine and similar drugs and to improve the quality of life for many cancer patients.
Project Terms: analog; Anti-Bacterial Agents; base; Basic Science; Biological Assay; Bypass; cancer cell; Cancer cell line; Cancer Patient; cell killing; Cell membrane; cell motility; Cells; Cessation of life; Charge; Chemistry; chemotherapy; commercialization; Communicable Diseases; Critical Pathways; Development; Disease; Drug Design; Drug resistance; effective therapy; Exposure to; gemcitabine; Goals; Growth; Human; Immunosuppressive Agents; improved; in vivo; inhibitor/antagonist; inorganic phosphate; Laboratories; Lead; Licensing; Literature; malignant breast neoplasm; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Malignant neoplasm of urinary bladder; Malignant Neoplasms; manufacturing scale-up; Measures; method development; Methods; Mono-S; Non-Small-Cell Lung Carcinoma; novel; novel strategies; nucleoside analog; Nucleoside Transporter; Nucleosides; Nucleotides; oncology; Outcome; Oxidases; oxidation; Pancreas; pancreatic cancer cells; Pancreatic Ductal Adenocarcinoma; Pathology; Pathway interactions; Pharmaceutical Preparations; Phase; phosphoramidate; Phosphoric Acids; Phosphorylation; Phosphotransferases; Plasma; Preparation; Procedures; Prodrugs; Property; public health relevance; Pyridoxal; pyridoxamine phosphate; Quality of life; Research; Safety; Survival Rate; System; Systemic Therapy; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Toxicology; United States; uptake; Variant; Viral Cancer; Vitamin B6; Work
