An Inhibitor of p53 as a Normal Tissue Protector Against Cancer Therapy
Abstract & Commentary
Synopsis: p53 is known as the "guardian of genome" in that it stimulates cell death when DNA damage has reached some threshold of irreparability. Normal cells exposed to irradiation or chemotherapy die in a p53-dependent fashion. An inhibitor of p53 has been developed (pifithrin-alpha) that appears to protect normal mice against the toxic effects of cancer chemotherapy and radiation therapy. But will it protect the tumor? Will it promote carcinogenesis?
Source: Komarov PG, et al. Science 1999;285: 1733-1737.
The p53 molecule is known as the guardian of genome because it is activated by things that damage the DNA of the cell and its activation usually leads to the death of the damaged cell. The death of normal cells as a consequence of exposure to cancer chemotherapeutic agents and gamma radiation is p53-dependent. The p53 is absent or mutated in more than half of human cancers. Its absence in tumors is associated with genomic instability and resistance to chemotherapy and radiation therapy. Most tumors that express either no or a mutated p53 have more aggressive growth characteristics and abnormal p53 is usually a poor prognostic factor where it has been studied.
Komarov and colleagues reasoned that if they could transiently interfere with p53 function in normal cells when an animal is exposed to DNA-damaging agents, it was possible that the death of normal cells could be averted. Of course, the paper would not have been published in Science if their hypothesis had been wrong! They developed a compound they called pifithrin-alpha (a neologism derived from a p-fifty-three inhibitor) that entered cells without difficulty and blocked the effects of normal p53. Using this molecule, they were able to block the proapoptotic effects of doxorubicin, etoposide, cytarabine, UV light, and gamma irradiation. Surprisingly, they also blocked cell killing by paclitaxel, a drug whose mechanism does not involve DNA damage and is not p53 dependent. Controls were included in which it is purported that p53-independent apoptosis is unaffected by the molecule; thus, the paclitaxel results are unexplained and not addressed further.
Komarov et al examined the effects of pifithrin-alpha in an in vivo model of total body irradiation in mice. They gave mice an approximate LD50 of radiation (the dose that would normally kill about half the mice) with or without pifithrin-alpha. The mice receiving the p53 inhibitor were not killed by the radiation exposure and did not lose weight the way mice did that were given the radiation alone. A formal "dose-modifying effect" was not established.
Commentary
Does this really make any sense? If it is in the tumor’s best interest to interfere with p53, how can it also be in the best interest of normal cells to do so? Is it really better to have normal cells, that sustain enough DNA damage that they would normally die, survive the genotoxic stress, and go on to try to replicate? It is important to point out that mice in which the p53 gene is knocked out have an extraordinarily high incidence of developing cancers. Similarly, when p53 is not functional as a consequence of an inherited familial genetic defect, the Li-Fraumeni syndrome is the result; it is characterized by a high incidence of a wide variety of neoplasms.
Frankly, this seems like one of those old movies where one of the characters says, "That idea is so crazy it just might work!" At this point, the data are not very impressive. Komarov et al should have been required to define the dose-modifying effect—i.e., the dose of radiation therapy that kills 100% of the animals in the presence of the drug divided by the dose of radiation therapy that kills 100% of the animals in its absence. Komarov et al should have also explained the effects on paclitaxel cell killing. In addition, an effort should have been made to see whether pifithrin-alpha influences the antitumor effects of drugs given in vivo. Finally, data on chronic administration and chronic follow-up should have been included to reassure us that pifithrin-alpha doesn’t promote the development of second cancers. But who knows? This idea is so crazy....
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