Identification of potential modulators of drug resistance

All preclinical model systems available will be employed to evaluate potential novel modulators for strong candidate genes and pathways in parallel with the final validation steps. In preparation for such studies some participating groups are already planning to address the topic of resistance modulation. The technology development and resources involved in such studies will be useful for further studies on resistance modulation. These proposed initial studies include:

  1. Inhibiting the function of proton pumps Pre-treatment with proton pump inhibitors (PPI) sensitizes tumor cell lines to cisplatin, fluorouracil and vinblastine. In vitro experiments will be aimed at defining the dose of PPI to obtain optimal control of the pH of the tumor cell microenvironment. The final aim is to initiate pilot clinical studies on the use of PPI in treatment of tumors in patients.
  2. Lysosomal cathepsins as targets of cells that are resistant to conventional chemotherapy. In some models of chemoresistance, an expanded acidic lysosomal compartment has been described, leading to sequestration of drugs in this compartment. The main goal of the project is to determine whether agents that induce lysosomal membrane permeabilization LMP will be efficient in inducing apoptosis of cells that are resistant to conventional agents such as cisplatin. In particular, the role of cathepsin enzymes (over expressed in many tumors) as potential targets of therapy will be investigated.. Agents that are capable of inducing cell death of tumor cells that are resistant to conventional anticancer agents will be tested in vivo.
  3. Preclinical studies of DNA repair inhibitors as chemosensitizers A series of compounds that are molecular combinations of MGMT inactivators with compounds that have been designed to target other DNA repair pathways have been synthesized. In addition, molecules that are combinations of alkylating agent and MGMT inhibitors have been produced. The ability of these compounds to inactivate the target processes and to sensitize human melanoma and lung cancer cells to therapeutic alkylating agents in will be determined. Agents that are effective as dual function agents in vitro will be further assessed in comparative studies in human melanoma and lung tumour xenograft models.
Page updated by Chemores May 23, 2007
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