Most patients with acute myeloid leukemia will undergo chemotherapy to treat the disease. But this treatment may be causing harm as well as helping, according to a new study.
Chemotherapy treatments for acute myeloid leukemia (AML), while essential for controlling the disease initially, actually may be contributing to the disease returning, a process that’s usually fatal.
Physicians and scientists at Washington University School of Medicine in St. Louis have found that the damage chemotherapy does to the DNA results in the recurrence of AML.
As such, this work adds fuel to the long-standing belief that chemotherapy-caused DNA damage creates new genetic mutations that let tumor cells evolve and get stronger, becoming resistant to treatment.
In the case of AML, chemo puts the cancer in remission at first. Without this treatment, most patients would die within a few months. Even with this treatment, though, 80 percent of patients don’t survive the disease that returns.
Scientists know that chemotherapy damages DNA in both healthy and cancer cells. However, there has been little direct evidence, until now, that the these drugs urge cancer cells to evolve and thus contribute to relapse.
Researchers suspect this phenomenon isn’t restricted to AML, and could hold true for other cancers as well.
In this study, scientists at Washington University’s Genome Institute examined the entire DNA – the genomes – of cancer cells taken from eight AML patients before and after relapse. Each patient received cytarabine and an anthracycline drug to push the cancer into remission. They also received other chemotherapy drugs to try to keep the cancer from returning.
Scientists used technology developed at the Institute to isolate DNA segments that had all mutations. These regions were then sequenced 600 times, an extraordinarily rigorous process to ensure the statistical accuracy of the results.
Researchers were somewhat surprised to learn that the cells from the relapsed cancer didn’t have a large number of new mutations. And while the cells from the cancer that returned had some new mutations, the overall percentage was modest compared to the number of mutations in the original tumor.
Scientists also found that the relapsed cells had a mutation that’s linked to DNA damage. This alteration was seen in significantly higher numbers (46 percent) in the relapsed cells, compared to 31 percent in the original tumor cells.
This suggests that the chemotherapy contributed to these mutations, the researchers concluded.
“The mutations in AML patients who have relapsed are different from those present in the primary tumor, and they are more likely to have a telltale signature of DNA damage,” says senior author John F. DiPersio, M.D., Ph.D, the Virginia E. and Sam J. Golman Professor of Medicine and chief of the division of oncology.
“This suggests that mutations in the relapse cells are influenced by the chemotherapy drugs the patients receive,” he adds.
“Chemotherapy drugs are absolutely necessary to get leukemia patients into remission, but we also pay a price in terms of DNA damage,” says co-author Timothy J. Ley, MD, the Lewis T. and Rosalind B. Apple Professor of Oncology.
“They may contribute to disease progression and relapse in many different cancers, which is why our long-term goal is to find targeted therapies based on the mutations specific to a patient’s cancer, rather than use drugs that further damage DNA.”
This research is published January 11, 2011 in the advance online edition of Nature.
According to the Leukemia and Lymphoma Society, there are over 245,000 people in the United States living with some form of leukemia, and over 44,000 new cases will be diagnosed each year. Among children with cancer, one out of every three will have some form of leukemia. However, over 90% of all cases of leukemia occur in adults.
Leukemia broadly defines a number of different cancers that originate in the bone marrow and blood cell lines, and typically produces an abnormal increase in the number of white blood cells in the body. Leukemias are subdivided into whether they are acute (occur rapidly) or chronic (develop over many years) and then further subdivided into what type of blood cell they start from, lymphocytic (usually from white blood cells that fight infection, like B-cells) or myelogenous (arising from cells in the bone marrow that eventually produce red blood cells). These categories make up the four most common types of leukemia:
- Acute Lymphoblastic (ALL): Affects adults over age 65 (50% survival); also the most common form of leukemia in children (85% survival)
- Chronic Lymphocytic (CLL): Affects mostly men over age 55 (75% survival)
- Acute Myelogenous (AML): Affects mostly adult men (40% survival)
- Chronic Myelogenous (CML): Affects mainly adults (90% survival)