Apr 11, 2012Science and Technology
Gene-targeting pharmaceutical lessens side effects of chemotherapy

A new, patented method may lessen the side effects of chemotherapy.The highly-studied, human p53 gene is known to play a key role in cellular stress response mechanisms by converting a variety of different stimuli into cell growth arrest or apoptosis (cell death). Such stimuli may include DNA damaging conditions, like gamma-irradiation, deregulation of transcription or replication, and oncogene transformation. 

Most anti-cancer therapies meant to target cancerous cells also damage or kill normal cells containing native p53, causing severe side effects. Specifically, radiation therapy and chemotherapy may cause severe damage to the lymphoid and hematopoietic system and intestinal epithelial tissue, which may limit the effectiveness of these therapies and may cause hair loss. Since such side effects are to a great extent determined by p53-mediated death of normal cells, the temporary suppression of p53 during the acute phase of anti-cancer therapy has been suggested as a therapeutic strategy to avoid these severe toxic events.

With an eye to this therapeutic strategy, the scientists at Quark Pharmaceuticals have disclosed an invention related to a pharmaceutical composition containing a double-stranded oligoribonucleotide compound, which down-regulates the expression of a human p53 gene. The patent discloses a method of treating a patient suffering from alopecia, acute renal failure or other diseases induced by chemotherapy or radiotherapy in which temporary (reversible) inhibition of p53 activity is beneficial. The present invention also contemplates treating other disorders that are accompanied by an elevated level of p53 polypeptide.

The patent discloses temporary suppression of p53 using the p53 siRNA, such that the novel siRNA molecules protect normal p53-containing cells from chemotherapy or radiotherapy-induced apoptosis. These siRNA molecules may also be used for inhibition of p53 expression in specific cancer cells where p53 inhibition potentiates apoptotic cell death in these cells. 


One of the primary issues with chemotherapy and radiation is that they are not selective -- they kill the good cells along with the bad. It is thus very desirable to create a system for narrowing these treatments’ effects to cancer cells exclusively. Other applications of this siRNA technology include treatment of acute renal failure, which is characterized by rapid deterioration of renal function associated with apoptotic cell death in the kidenys, and other conditions in which p53 is activated as a consequence of a variety of stresses associated with injuries including burns, hyperthermia, myocardial infarction, stroke, and ischemia. Temporary p53 inhibition using the siRNA molecules can be therapeutically effective in reducing or eliminating p53-dependent neuronal death in central nervous system, brain and spinal cord injury; the preservation of tissues and organs prior to transplanting; preparation of a host for a bone marrow transplant; and reducing or eliminating neuronal damage during a seizure. In addition, the p53 gene plays a role in cell aging.  In particular, morphological and physiological alterations of normal tissues associated with aging may be related to p53 activity. Senescent cells that accumulate in tissues over time are known to maintain very high levels of p53-dependent transcription. p53-dependent secretions of growth inhibitors by senescent cells accumulate in aging tissue. Thus, the siRNA molecules disclosed in this patent may also be used in suppression of tissue aging.


Since long-term p53 inactivation can significantly increase the risk of cancer, the inhibition of p53 using the molecules is temporary. This may be a difficult balance to achieve, however, and therefore raises concerns that, in attempting to avoid the side effects of cancer treatments, the patient will only increase his risk of cancer. This switching off and on of the gene must therefore be well regulated before it is made available to the public. 

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