Lung cancer is the leading cause of cancer death in the United States. Small cell lung carcinoma is the most aggressive type of lung cancer and is responsible for the high mortality. Because of the size and distribution of small lung cancer, cytoreductive surgery is not very effective for this disease and therefore chemotherapy and/or radiation are the treatment of choice. However, the efficacy of chemotherapy in lung cancer is limited by the fast development of cancer cell resistance during the treatment. Development of resistance demands significant increases in the doses of the toxic anticancer drug, thus producing adverse side effects upon healthy organs. Two main mechanisms are responsible for the observed resistance: pump and nonpump resistance. Pump resistance is caused by membrane efflux pumps that decrease the anticancer drug concentration inside the cells. The main transporters responsible for the pump resistance in lung cancer cells are the members of the so-called """"""""multidrug resistance associated proteins"""""""" (MRP). P-glycoprotein efflux pump does not play an important role in lung cancer resistance. Nonpump drug resistance is primarily attributed to the activation of antiapoptotic cellular defense and BCL2 protein is a key player in this defense. The main objective of the proposed research is to mitigate the above described resistance through the development, manufacture, characterization and in vitro and in vivo evaluation of a novel drug delivery system which contains four main components: (1) liposomes as a carrier;(2) anticancer drug (doxorubicin);(3) suppressor of pump drug resistance (antisense oligonucleotides or siRNA targeted to MRP1 and MRP2 proteins);(4) suppressor of nonpump cellular resistance (antisense oligonucleotides or siRNA targeted to the BCL2 protein). In addition to the simultaneous suppression of pump and nonpump cellular resistance the use of proposed liposomal drug delivery system allows for inhalatory local delivery of active components directly to the lungs minimizing adverse side effects. We hypothesize that simultaneous suppression of pump and nonpump cellular resistance will significantly increase the efficacyof chemotherapy of resistant lung cancer. The proposed drug delivery system utilizes a novel two-pronged molecular targeting strategy (simultaneous targeting of proteins that are key players in cellular pump and nonpump resistance). This will permit us to increase the efficacyof cancer chemotherapy by simultaneous suppression of pump and nonpump resistance.
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