| dc.description.abstract | Breast cancer is the most common cancer in women worldwide and its incidence is increasing, particularly in developing countries. The survival rate of early stage breast cancer is 80% but falls to 24% for breast cancers diagnosed at a more advanced stage. Leukemia is a cancer that begins in the bone marrow and results in abnormal white blood cells or leukemia cells. The five-year survival rate is only 57% in the US. Current therapies affect every cell, healthy or not, and generate physical and psychological consequences in the patient.
Our approach is to target breast cancer cells and leukemia cells with a protein, annexin A5, and kill them specifically with an anti-cancer drug. Annexin A5 binds to phosphatidylserine, a marker of cancer cells expressed on the outer leaflet of the plasma membrane. Chlorambucil, or Leukeran (4-[bis(2-chlorethyl) amino] benzenebutanoic acid) is a drug used in chemotherapy treatment to treat leukemia; several molecules of this alkylating agent are linked by their carboxylic functional groups to primary amines of the protein by EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide).
The mass of the conjugate was compared to the mass of annexin A5, and the quantity of chlorambucil on the protein has been determined. In vitro cytotoxicity assays were made on two breast cancer cell types, EMT6 and 4T1, and two leukemia cell types, L1210 and P388. The cytotoxicity of the conjugate was compared to the cytotoxicity of chlorambucil alone, showing a significant improvement with a LD50 (median lethal dose or amount of the substance required to kill 50% of the cells) 10 or 100-fold times less than the free chlorambucil. In vivo experiments have been made with 4T1 and L1210 cells on BALB/c mice, and the survival and physiologic measurements were made. The results showed that the conjugate increased the survival time in both cancers. | en_US |
