Antitumor agent under the microscopeOctober 30, 2000Mechanical stabilization of DNA keeps tumor cells in check Cisplatin is one of the most widely employed cancer medications. As with many other chemotherapy agents, the mechanism by which it works has not been fully researched. Now, thanks to Munich physicists Hermann E. Gaub, Rupert Krautbauer, and Hauke Clausen-Schaumann, an important step toward understanding has been taken. Cisplatin acts as an antitumor agent by inhibiting cell division. The uncontrolled proliferation of tumor cells can be slowed, some tumors can even be made to shrink with this antitumor agent. It has been known for some time that cisplatin binds to the double strands of DNA, making connections between neighboring building blocks both within a single strand or between both strands. But what does this mean for the DNA? Gaub and his coworkers took a closer look at DNA both with and without cisplatin. The method of choice was atomic force microscopy. For this, individual strands of DNA were placed on a gold substrate and then stretched between the gold and the tiny tip of an atomic force microscope. The instrument recorded the force expended versus the degree of stretching of the DNA. The striking realization: cisplatin considerably alters the mechanistic properties of the genetic molecule. Previous experiments with double-stranded DNA have demonstrated that the molecules can be severely overstretched without tearing. Initially, a change of structure occurs. As the molecule is stretched further, the double strand separates into two single strands. When relaxed, the molecule returns to its original structure. The inclusion of cisplatin causes the DNA to be much more stable when stretched. In fact, cisplatin can completely hinder strand separation. When reading genetic information, the enzymes involved have to exert relatively strong forces on the DNA in order to unwind the double helix and separate the two strands from each other in the spot to be read. This is the only way to get at the information. It is thus obvious that cisplatin mechanically stabilizes DNA, making it unreadable. If the DNA can not be read, the cell can no longer divide. This puts the brakes on tumor growth. WILEY-VCH Verlag GmbH |
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