| Popis: |
The origin of the common phrase “your name is mud” may derive from the ordeal of 19th century physician, Dr. Samuel Mudd, who was perhaps wrongly convicted of conspiracy in the assassination of President Abraham Lincoln. Mudd’s crime may have only been bad luck: Lincoln’s assassin, John Wilkes Booth, allegedly previously unknown to the doctor, had broken his leg and happened across Mudd who, unwisely, as it turned out, set the fracture, and his own subsequent fate, which included life imprisonment with hard labor, making him a potential victim of circumstance rather than the perpetrator of a crime. Mudd’s grandson, also a physician, tried unsuccessfully to clear his grandfather’s widely reviled name, which as a result has remained, both literally and figuratively, Mudd. This historical analogy highlights the important point that radiosensitizers as a class have been ignored rather than adored due to their failed reputation. Hence, in the field of radiation oncology, the “your name is mud” expression applies to radiation sensitizers, which from hyperbaric oxygen and the nitroimidazoles, to motexafin gadolinium, tirapazamine and efaproxiral have generally overpromised and under delivered with respect to survival treatment benefits in multiple different indications. However, newer non-toxic radiosensitizers on the horizon such as the antienergetic epigenetic redox modulator, RRx-001, that will start a Phase 2 clinical trial with concurrent whole brain radiotherapy (WBRT) in subjects with brain metastases, may finally validate the underlying promise and unrealized potential of these agents. The successful treatment of brain metastases is at least a four-hurdle process involving penetration, retention, selectivity and toxicity. This article will review the mechanism of the radiosensitizers, RRx- 001, and 2-deoxyglucose, as examples or “role models” for therapies that theoretically are able to overcome these substantial in vivo obstacles to successfully treat brain metastases. It is the thesis of this review that new radiosensitizers are urgently needed and their poor reputation should be overcome. |
