Highly Effective Chemoprotective and Radioprotective Drugs from DKFZ Heidelberg
DKFZ Deutsches Krebsforschungszentrum
- Chemo/radiotherapy-induced side effects limit the applicable doses during cancer treatment
- Rocaglamide A (Roc-A) and derivatives show chemo- and radioprotective efficacy in highly proliferating cells like hematopoietic progenitor cells, in slowly proliferating cells like cardiomyocytes and in quiescent cells like T and B cells.
- Roc-A and derivatives are highly specific for normal cells and do not protect p53-deficient/mutated cancer cells
- Roc-A has a wide therapeutic window and is highly potent (nM range)
The efficacy of chemo- and radiotherapy is limited by adverse side effects like neutropenia. Reducing these side effects would allow dose escalation and would therefore lead to a more efficient eradication of the tumor by radiation and chemotherapeutics. Only a few chemo/radioprotective drugs are clinically available. Moreover, the majority of drugs have major drawbacks. For instance, the only FDA-approved radioprotective drug Amifostine (Ethyol®) is unspecific in many therapeutic settings and exerts its effects only at micromolar concentrations. The current technology provides Rocaglamide A (RocA) and other derivatives as specific and highly potent chemo/radioprotective drugs with a wide therapeutic window.
In in vitro assays the chemoprotective efficacy of Roc-A was tested by 8-fold increased exposure of malignant and non-malignant cells to Etoposide. Increasing the Etoposide dose led to a 3-fold increase in cell death. With the co-application of Roc-A, non-malignant cells were not affected by the Etoposide dose increase. Similar results were obtained for ionizing radiation. In vivo experiments are ongoing.
The chemoprotective and radioprotective potential of Roc-A is based on the fact that Roc-A prevents the death of healthy cells by inhibiting p53 expression at the translational level (see Reference).
Applications and Commercial Opportunity
DKFZ is looking for a licensing or collaboration partner for its technology to further develop these promising chemo/radioprotective drugs.
The inventors are Min Li-Weber, Michael S. Becker and Peter H. Krammer, all employees of DKFZ.
A European patent application was filed in November 2013.
Becker et al. “The traditional Chinese medical compound Rocaglamide protects nonmalignant primary cells from DNA damage-induced toxicity by inhibition of p53 expression”, Cell Death Dis. (2014); 5:e1000.