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Alcohol: Clin Exp Res ; 12 :7— Choose fields to export. Select All. Close Proceed. Export to Mendeley. Get permanent URL for this record. Please provide a name for this query:. Saved to Workspace! Close Go to Workspace. Email Results. Email URL only? Number of results:. Email Format:. More than half of the 32 P retained by the cells that were incubated with 32 P[PO 4 ]for 24 h and then grown in non-radioactive medium for 48 h before the DNA was extracted had been permanently incorporated into cellular DNA.
To determine whether cell death involves apoptosis as well as necrosis, mouse CRL cells or HeLa S3 cells were incubated with varying amounts of 32 P for 24 hours, replaced with non-radioactive medium for an additional 24 hours, and the cells analyzed by western blot for the presence of cleaved caspase-3 indicating apoptosis Fig 3B.
The CRL cells clearly demonstrated that apoptosis was involved in cellular death, while the HeLa S3 cells showed no detectable cleaved caspase-3 data not shown. Antibody directed against beta-actin was used to verify equal loading of protein amounts in the gel wells. HeLa S3 cells express E6 from HPV18 and are rendered p53 null which severely inhibits apoptosis functions [ 28 , 29 ].
Mouse CRL or human HeLa S3 cell lines were incubated overnight with 32 P[PO 4 ] and then grown for 48 h in non-radioactive medium lanes 1 through 4 , or grown for 24 h in non-radioactive medium, grown for 24 h with 32 P[PO 4 ], and then grown for 24 h in non-radioactive medium lanes 5 through 8 , or grown for 48 h in non-radioactive medium, then grown for 24 h with 32 P[PO 4 ] lanes 9 through Apoptosis induced by 32 P in mouse CRL cells.
Mouse CRL cells were incubated with 0, 2. Protein was extracted from each well and analyzed for apoptosis by western blots using antibody to cleaved caspase-3 protein Lanes 1 through 5. Antibody against beta-actin was used to verify identical amounts of protein were loaded lanes 6 through There were no apparent detrimental effects of [ 32 P]PO 4 comparing the weight of the treated mice to the control groups data not shown.
Inset: Representative picture at 35 days post CRL cell injection, showing two control mice on the left, and one mouse that received one 5 uCi [ 32 P]PO 4 dose right.
This study documents our discovery that a single intravenous dose of the 32 P radioisotope significantly inhibits the growth of pre-established tumors in a murine syngeneic model, while simultaneously establishing the mechanism underlying this anti-cancer effect.
Specifically, we show that aqueous 32 P is incorporated into nascent DNA, where isotopic decay shears both strands, causing double-strand breakage as proven by phosphorylation of the histone H2-AX. Our in vitro experiments also demonstrate that the pure beta-emitter 32 P is superior to the more powerful pure beta-emitter 90 Y in tumor cytotoxicity, and finally, that apoptosis contributes to this cytotoxicity.
Fig 5 depicts a proposed mechanism for 32 P-induced cell killing. In this schematic, 32 P is incorporated directly into one strand of replicating DNA. Next, the electron released by this decay event needs to travel only 2 nm to reach the contralateral strand of the double helix, severing it and thus causing a double-strand break at this genomic locus. This mechanism stands in stark contrast to non-incorporated beta-emitting radioisotopes, where only a small fraction of emitted electrons travel in the precise orientation necessary to strike one strand plus its opposite strand and cause a double-strand DNA break [ 30 , 31 ].
With 32 P, the extreme proximity of the contralateral target strand to the decay-produced electron makes this double-strand breakage much more likely to occur [ 32 ]. The radioisotope is incorporated into the ribose-phosphate backbone of DNA in dividing cells. Although an emitted electron that travels in the perfect orientation from this 32 P decay to sever the opposite strand will only occur at a low percentage of the time, it is still much higher and more efficient than those electrons which are generated by other beta-producing radioisotopes on the cell surface or in the cytosol that must travel distances that are usually one thousand times or more longer in length.
Aqueous [ 32 P]PO 4 offers many potential advantages over other anti-cancer therapeutic agents. Firstly, it allows for rapid systemic distribution and incorporation into primary tumors and 32 P is preferentially absorbed by rapidly proliferating cells, such as cancer cells. In addition, [ 32 P]PO 4 improves on the previous direct injection of particulate colloidal 32 P into primary tumors, since aqueous [ 32 P]PO 4 allows for a simple intravenous injection [ 33 — 35 ].
Secondly, 32 P is already an FDA-approved drug, with a known low toxicity profile [ 36 ]. Previous clinical studies of 32 P-orthophosphate [PO 4 ] in aqueous solution for polycythemia vera and essential thrombocythemia have established tolerable dose levels, particularly with respect to myelosuppression [ 36 ].
In this context, it is noteworthy that no obvious toxic side effects occurred in any of the model systems we have studied to date. Moreover, this new indication and method of use for an existing drug saves considerable time and expense, relative to the investment required for new anticancer agents.
Thirdly, in contrast to other beta-emitting isotopes such as I and 90 Y, 32 P is incorporated directly into nascent DNA [ 40 , 41 ]. Our data suggest that this incorporation dramatically increases the cell-killing efficiency of 32 P, since the decay of incorporated 32 P to sulfur chemically breaks the first strand of the DNA and the released electron needs to travel only 2 nm to reach its contralateral DNA strand.
Thus, this process efficiently causes double-strand DNA breakage, which is required to overcome innate DNA repair pathways and achieve cell death. In contrast to 32 P, other electron-emitting isotopes such as I and 90 Y emit electrons from distances of 1, to 5, nm away from DNA, some to 2,fold farther than the distance of an incorporated 32 P atom from its sister DNA strand [ 42 — 44 ].
This same principle may operate with 32 P as an anti-cancer agent. The decay of 32 P to sulfur chemically shears the strand of DNA into which it is incorporated. We hypothesize that this event, coupled with the extremely close proximity of the incorporated radioisotope to its sister DNA strand, results in a dramatic increase in cell-killing efficiency vs.
The resulting implications for the potential clinical treatment of primary human tumors are obvious and far-reaching. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract Radioisotopes that emit electrons beta particles , such as radioiodine, can effectively kill target cells, including cancer cells. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Data Availability: All relevant data are within the paper.
Introduction Beta particles electrons emitted by radioisotopes are known to efficiently kill cancer cells. Assay for apoptosis in cell lines incubated with 32 P. Results Cells exposed to [ 32 P]PO 4 were compared with those exposed to identical counts per minute of the more powerful beta-particle emitter, 90 Y, after which WST-1 cell proliferation assays were performed Fig 1. Download: PPT. Fig 1.
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