RNA provides a potentially versatile target for the detection and treatment of cancer, and scientists are finding creative new ways to use it therapeutically. Nearly one dozen antisense therapies directed against an array of cancers are proceeding through early- to late-phase clinical trials.
John-Stephen Taylor, Ph.D., a chemist at Washington University in St. Louis, Mo., is using RNA as a trigger to set off the catalytic release of chemotherapeutic drugs. He has essentially built a chemical machine that, when it binds to a disease-specific messenger RNA, sparks the release of a cytotoxic drug inside the cell.
When designing this system, Taylor wondered how genetic information available through microarrays could be used to selectively target cancer cells even if nothing was known about the biology of that cell.
In the day-to-day operations of both normal and cancer cells, RNA works as a chemical messenger, telling the cell which proteins to make. Scientists trying to beat cancer at its own game have tried to target and disrupt that message. For example, antisense therapy prevents cells from making a specific protein. Taylor looked for a way to use mRNA instead as a stimulus. His solution is to screen cancer cells on a DNA chip to identify a unique or overexpressed mRNA sequence and then synthesize a complementary strand of oligonucleotides that will bind to that sequence.
The oligonucleotides will then be modified to hold two components, a dormant form of a drug, called a prodrug, and a catalyst to activate the prodrug. When this nucleic acid payload enters the cell and binds to the target mRNA, the dormant drug and catalyst come together, initiating a chemical reaction that releases the drug and kills the cell.
"The idea itself is very simple," said Taylor. "The tricky part will be implementing various components so they can work together inside the cell."
Indeed, the design remains under painstaking constructionthis nano-tiny system has yet to see the inside of any cell. Taylor is working to attach TAT peptide, a recognition molecule that will allow this payload to slip past the protective border of the cells outer membrane. The TAT sequence is not specific enough to distinguish cancer cells from normal cells, so Taylors system will enter every cell in the body. The drug would only be activated in cells that carry the unique or over-expressed mRNA sequence because that is the only place the oligonucleotide will bind. Normal cells would be unharmed because they would lack the sequence for the complementary message.
"In my system, Im not trying to destroy that message," Taylor said. "The beauty of it is, I dont have to know what that message is for. All I need to know is that the cancer cell can be distinguished from all other cells in the body because it has either a unique sequence or a uniquely overexpressed sequence," said Taylor. "If there are 10 more copies of this sequence, then I will get 10 more copies of this cytotoxic drug released in this cell."
Because the chemistry of chemotherapy drugs can be altered to render them inactive, and thus converted into a prodrug, said Taylor, he hopes to use this system against many types of cancer. For example, the cytotoxic drugs daunorubicin and 5-fluorouracil could be used in the prodrug/catalyst system Taylor is currently testing.
In work published in 2000, Taylor set up a model system that worked in a test tube. He linked imidazole, which he used as a catalyst, to the 5' end of a nucleotide sequence, and linked p-nitrophenol ester, which he used as a "prodrug" to the 3' end. When the imidazole catalyst and p-nitrophenol ester "prodrug" were mixed with a complementary stretch of oligonucleotides, the imidazole catalyzed the release of p-nitrophenol. Release of p-nitrophenol is a crucial step in converting prodrugs, such as 5-fluorouracil, to active drugs. Release of p-nitrophenol is a crucial step in converting a newly designed class of prodrugs to active drugs, such as 5-fluorouracil, daunorubicin, and nitrogen mustards. In Taylors drug releasing system, for example, the "prodrug" form of daunorubicin would be "unlocked" and released into an active drug by the catalyst "key" (see graphic, p. 1830).
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To deliver a therapeutic load of chemotherapy drugs he is teaming up with fellow Washington University chemist Karen Wooley, Ph.D., who designed synthetic polymers that will hold a lot of the PNA construct.
Putting this system to therapeutic use could take several decades, but Taylor does have a vision for personalized chemotherapy. A patient would have a biopsy analyzed over a DNA chip to identify uniquely expressed sequences. That information would go into a second machine, which would assemble the PNA-prodrug complex using a chemotherapeutic agent already in use. "Its a general approach that could provide a universal way to treat any cancer or viral disease," said Taylor. "The next step is to test this system inside a breast cancer cell line."
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