Cyclophosphamide became known in the mid-1900s for its ability to help cure lymphoma in children. Today, researchers have a better understanding of how the drug works and its ability to combat cancer. In a recent paper published in Cancer Discovery, researchers showed that cyclophosphamide is able to both kill cancer cells and trigger the immune system, causing it to attack diseased cells. These findings are helping researchers better understand how immune cells are activated to fight cancer. 

Cyclophosphamide is an alkylating agent, one of the oldest and most common types of chemotherapy used by oncologists. Now used to treat several types of cancer, it was originally used to treat Burkitt’s lymphoma, named for the doctor who first used the drug to fight this form of lymphoma. Prior to Burkitt’s work, the disease had a 100% mortality rate. 

Alkylating agents work by attaching chemical components, called alkyl groups, to the DNA in cancer calls, causing breaks in the DNA. This makes it impossible for the cells to duplicate their DNA and divide, which, in turn, stops cellular growth. But research over the years has shown that while high doses were more effective than low doses against certain cancers, they inflicted a similar amount of DNA damage. This led researchers to believe something else was going on when high doses were being administered. 

The recent study showed the effect high doses of cyclophosphamide had on macrophages. Macrophages are cells that can attack infected or dying cells. The results in mouse models implanted with human lymphoma tissue showed that high doses of the drug damaged tumor cells in a way that stressed the lymphoma cells. The stressed cells secreted cytokines, substances that summon macrophages to destroy tumor cells. They also found that macrophages expressing the CD36 and FcgRIV proteins had the largest appetite for the stressed lymphoma cells. 

While high doses of cyclophosphamide and other alkylating agents may be too toxic for patients, researchers are looking into other drugs that mimic the tumor stress with milder side effects.