Inflammation can help you fight invading microbes, but it can also kill you, which leads to insufficient blood circulation and the same organ failure. A new study shows that some drugs against cancer may be able to allay excessive inflammation that occurs in conditions such as sepsis, which is responsible for over 250,000 deaths in the US each year.
Inflammation is a normal immune response to a pathogenic threat, involving the production of various chemical signals and activation of immune cells such as neutrophils. Yet its effects can kill on a massive scale. Researchers suspect, for example, that the 1918-1919 pandemic flu, which killed more than 40 million, was so deadly because it sent an inflammation spiral out of control. Over-the-top Inflammation is also a characteristic of sepsis, wherein the body overreacts to an infection. There are a few options for treating people with sepsis, which can cause organs to stop working and can be fatal within hours.
molecular biologist Ivan Marazzi Ichan of Medicine Mount Sinai School in New York and his colleagues set out to discover how different cells control the activity of genes that promote inflammation. They exposed human cells and mouse to one of the two viruses, activation of immune cell genes. The team then tested many different compounds that affect how DNA is packaged in cells, the idea being that the compounds could alter the activity of these genes. One of the compounds which hindered gene activity, camptothecin is a cancer treatment. Among the compounds tested, said Marazzi. "It would probably have been the last" he would have expected to work.
Camptothecin kills cancer cells by blocking the enzyme topoisomerase I, which eliminates kinks from DNA so it can be duplicated or read to produce proteins. The findings of the team suggest that topoisomerase I also helps orchestrate the immune response to pathogenic attack.
To determine whether blocking topoisomerase I could counteract the inflammation out of control, the researchers injected mice with a poison that triggers bacterial septic shock, a severe form of sepsis, and then assayed some of mice with camptothecin. All untreated mice died within 40 hours, while 0% of the mice that received camptothecin survived, the researchers report online today in Science . The drug has also allowed 70% of the mice to live by infection with the bacterium Staphylococcus aureus , which can cause sepsis in humans. Only 11% of untreated animals survived the infection. People with influenza are particularly susceptible to bacterial infections that can lead to sepsis. Marazzi and his colleagues found that mice protected captothecin suffering from these infections, saving 94% of them, while all untreated mice died.
The study "provides a very interesting and promising strategy," said immunopathologist Peter Ward of the University of Michigan, Ann Arbor, who was not connected to the research. But he wants to other animal studies to confirm that blocking topoisomerase is effective against other types of bacteria that most often cause septicemia in people.
the results are encouraging, says molecular biologist Murat Kaynar of University of Pittsburgh School of medicine in Pennsylvania. However, he warned that many potential treatments for sepsis that were promising in animal studies do not pan in human studies. "We've had many attempts have failed," he said.
Although the topoisomerase I enzyme is not a specialized immune system, the researchers found that it has a great impact on certain genes that control inflammation, said molecular immunologist Stephen Smale University California, Los Angeles. Thus, "the study by Marazzi and his colleagues shows the value to broaden the search for inhibitors inflammatory responses," he said.
Camptothecin is one of several topoisomerase I-inhibitor drugs cancer who have received approval from the Food and Drug administration. Marazzi said he and his colleagues are working with a pharmaceutical company to organize a clinical trial to test whether blocking topoisomerase I is beneficial in sepsis. Although such inhibitors can trigger problems such as bleeding and infection, with sepsis patients would only need a small number of doses, so these side effects are less likely, Marazzi predicted. "We have a potential treatment for a deadly disease that kills millions of people worldwide. "
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