Mechanisms of Anti-Cancer Drugs

Many anti-cancer agents work by binding to DNA. We have characterized DNA sites targeted by interstrand cross-linking agents and probed structural abnormalities induced by cross-linking. We are currently most focused on diepoxybutane, the active form of the prodrug treosulfan, which is used to treat ovarian cancer. Related compounds of interest include nitrogen mustard, the first synthetic compound used in cancer chemotherapy, and epichlorohydrin, widely used in the synthetic polymer industry.

Characteristic comet shapes after treatment  of human leukemia cells with hydrogen peroxide.

One project currently underway investigates whether the DNA products formed by some anti-cancer drugs, such as cisplatin, may lead to mutagenesis. This might help explain why patients who receive cancer chemotherapy have higher rates of cancer many years after treatment.

Another ongoing project quantifies cross-linking by anti-cancer drugs in leukemia cells. Treatment with hydrogen peroxide leads to “comet” shapes of single cells after electrophoresis, but cross-links reduce the length of the comet tail.

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