Chemotherapy drugs are able to fight inflammation

Topoisomerase 1, known for its role in unwinding DNA during transcription and the target of chemotherapy drugs Camptosar (irinotecan, Pfizer Inc.) and Hycamtin (topotecan, GlaxoSmithKline plc.), plays a role in coordinating the innate immune response, and inhibiting it could be a therapeutic strategy in diseases characterized by excessive inflammation, scientists reported in the April 29, 2016, issue of Science.

Senior author Ivan Marazzi, assistant professor of microbiology at the Icahn School of Medicine, toldBioWorld Today that the link between topoisomerase and innate immunity was unexpected. Topoisomerase inhibitor camptothecin was “the last inhibitor I would have thought would work” to curb excessive inflammation, he said.

Acute inflammation is the major weapon of innate immunity, the immune system’s first responder. If it does not end in a timely manner, though, it can be worse than the diseases it is deployed against. Infectious diseases with a high mortality rate, from the 1918/1919 pandemic influenza virus to Ebola, are dangerous in part because the innate immune system damages the lungs, blood vessels and other organs. (SeeBioWorld Today, Jan. 18, 2007.)

Sepsis is also characterized by out-of-control inflammation. Opinions differ on whether that inflammation needs to originally be caused by an infection, or whether other shocks to the system, such as an accident, that somehow set off a DEFCON 1 response by the innate immune system comprise true sepsis. But no matter how it is defined, once sepsis gets its start it causes extremely high mortality. Estimates begin somewhere in the double digits and range up to 50 percent.

Acute inflammation of a single organ, such as pancreatitis, can also spiral out of control and lead to multi-organ failure. (See BioWorld Today, Jan. 13, 2016.)

What all those conditions have in common is that treatments for them are nonspecific and mostly supportive. “We don’t know how to deal with this kind of extreme inflammation,” Marazzi said.

In their experiments, Marazzi and his team were testing whether chromatin-targeting drugs would affect the gene expression changes that resulted from bacteria. “There has been a boom in epigenetic therapy,” he said, and in previous work, his team had shown that BET bromodomain inhibitors – a class of chromatin-targeting drugs being developed as cancer treatments by Resverlogix Corp. and others – also showed the ability to curb inflammation in cell culture.

Instead of going targeted to look at a certain class of inhibitors, Marazzi said, he and his team “designed an assay that could tell us whether a drug was working on chromatin or naked DNA.”

Among the compounds they tested that were able to affect the innate immune gene expression signature was the topoisomerase I inhibitor camptothecin. In more detailed follow-up, the team determined that topoisomerase I helps recruit the transcription enzyme RNA polymerase II to innate immune genes, and showed that another topoisomerase I inhibitor, topotecan, had the same effects as camptothecin.

The team next tested topotecan in three separate mouse models of sepsis, caused by bacterial infection, bacterial-viral co-infection and acute liver failure, respectively. In all three cases, the majority of topotecan-treated animals survived illness severe enough to kill control animals.

In human cells, inhibiting topoisomerase I was also able to counteract the pro-inflammatory effects of Ebola virus, another disease characterized by a massive inflammatory response, and influenza virus.

At the doses used for chemotherapy, camptothecin kills cells, pushing them into apoptosis by inducing irreparable amounts of DNA damage.

For curbing inflammation, however, only one or two doses were necessary. Those doses were also only a fraction of the dose used in chemotherapy, making it “very likely” that the drug would be well tolerated in a clinical setting, Marazzi said.

Mount Sinai has filed a patent on the use of topoisomerase I inhibitors for treating inflammation.

Marazzi and his team are currently working to understand the mechanism of how topoisomerase I, which is a very general housekeeping enzyme for DNA transcription, has specific effects on inflammation.

They have also created modified versions of camptothecin and topotecan, and are testing those compounds “over a battery of conditions that are linked to cytokine storm,” he said.

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