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In today¿s Proceedings of the National Academy of Science, researchers from the University of Mississippi, Louisville and the University of Texas describe a new anticancer drug that selectively binds to rare "left-handed" DNA and kills multidrug-resistant cancer cells. The familiar Watson-Crick double helix of DNA, called B-DNA, winds in a right-handed direction. But like a screw, the helix can wind the other way: under certain conditions, DNA adopts a left-handed form, called Z-DNA. Despite great interest, little is known about the biological function of Z-DNA, or other unusual forms of the molecule, including triplex and tetraplex DNA. But researchers do know that in the cell, Z-DNA forms when DNA gets transcribed.
In 37 painstaking steps, the authors of this latest report synthesized an exact mirror image of a well-known anticancer drug, daunorubicin, used to treat acute leukemias. Normally, this drug binds to B-DNA, preventing the DNA from being duplicated. As a result, it prevents cells from multiplying out of control¿the root cause of cancer. The researchers found that¿even though Z-DNA is not a perfect mirror image of B-DNA¿the mirror-image drug still bound specifically to left-handed Z-DNA. And in addition, it converted a mixture of B- and Z-DNA into pure Z-DNA.
In a preliminary study, the researchers then tested how poisonous the new drug was¿compared with a related, right-handed compound called doxorubicin¿by administering it to two different cancer cell lines, one that is sensitive to drugs and one that is multidrug-resistant. On the sensitive cells, the new drug was not as effective as the right-handed drug, but it was five times better at killing the resistant cells. Although they cannot be certain, the researchers therefore suspect its potency might stem from its ability to bind to left-handed DNA. Whether drugs binding to left-handed DNA will ultimately define a new class of anticancer drugs remains to be seen, but they surely provide a tool for studying Z-DNA in the cell.