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Attenuation of chemotheraphy side effects in hematopoietic cancer

Technology Number: 

1686

Principal Investigator

Prof.
Menachem
Rubinstein

Department: 

Molecular Genetics
Summary 

Applications


  • Co-treatment with chemotherapy
  • Co-treatment with statin treatmen

Advantages


  • Lower collateral toxicities allow for greater flexibility in treatment dosage.
  • Enhanced patient survival rate.
  • More favorably considered as a line of therapy due to decreased side effects.
  • Utilization of well-characterized compounds alleviates safety and toxicity considerations.

Technology's Essence


ER stress, elicited by chemotherapeutic agents such as doxorubicin, 5FU, vincristine and bortezomib, or statins such simvastatin, triggers cell death at least in part through generation of leukotriene C4 (LTC4), which induces ROS accumulation, DNA damage and subsequent cell death. LTC4 can be produced by two parallel pathways. Cells of hematopoietic origin express C4 synthase (LTC4S) and secrete their LTC4 load, thereby affecting nearby tissues. In contrast, as discloses by the present invention, non-hematopoietic cells generate LTC4 by the enzyme MGST2 (an isoenzyme of LTC4S), and retain it to act internally leading to their demise. This difference is the basis for the present invention. Thus, LTC4 receptor antagonists (montelukast, pranlukast, etc.) will alleviate the toxicity of chemotherapy towards non-hematopoietic tissues and cells, but retaining the therapeutic effectiveness of chemotherapy on lymphocytic leukemia, lymphoma and myeloma patients. In conjuction, it was found that pranlukast attenuated cell death triggered by a broad range (0.5-4 µg/ml) of simvastatin (a statin) concentrations.

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