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Attack of the Alkylating Agents

Old Chemo Drug at High Doses Goads Immune System to Fight Lymphoma

In a paper in the July 2 issue of Cancer Discovery, researchers from the Dana-Farber Cancer Institute demonstrate that large doses of cyclophosphamide not only kill cancer cells directly, as was previously known, but also spur an immune system attack on the cells. Their discovery shows how cyclophosphamide and other alkylating agents, which are among the oldest and most widely used types of chemotherapy, actually work, and indicates a novel way of getting the immune system to strike certain cancers.

Cyclophosphamide was only the eighth anti-cancer drug when it was approved by the FDA in 1954. It became a mainstay of cancer treatment after British physician Denis Parsons Burkitt and others used high doses to cure children with Burkitt lymphoma, which had a 100% mortality rate at the time, sometimes with a single dose. Nowadays, lower doses of cyclophosphamide and other alkylating agents are used to treat breast, ovarian, and pediatric cancers, among others.

Alkylating agents attach what are called alkyl groups to cancer cells’ DNA, which causes breaks in the DNA molecule. This weakens the cells’ ability to duplicate their DNA and divide.

In the new study, investigators focused on the effect of high doses of cyclophosphamide on macrophages, which, when conditions are right, eat infected cells or cells that are dying. In mouse models implanted with human lymphoma tissue, high doses of cyclophosphamide, but not normal doses, damaged tumor cells in a way that severely stressed the lymphoma cells. These cells responded by secreting cytokines, which results in the macrophages eating the tumor cells.

Thousands of these macrophages were examined to determine which genes were active, or expressed, in each of them. The researchers found that one subset, which expresses CD36 and FcgRIV proteins, is particularly attracted to stressed lymphoma cells.

Although high doses of cyclophosphamide and other alkylating agents may be too toxic for patients with diseases other than Burkitt lymphoma, researchers are investigating agents that can also stress cancer cells, but with milder side effects.

The findings may be particularly important for patients who have “double-hit” lymphomas, which are known for their aggressiveness. There is a lack of targeted therapies for this disease, which accounts for 6% to 10% of diffuse large B-cell lymphomas and generally has poor outcomes.

Source: Dana-Farber Cancer Institute, July 2, 2019

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