A new study published in the Journal of Clinical Oncology tries to answer why anthycyclins, a class of drugs used to treat acute lymphoblastic leukemia and other cancers in children, cause some patients to suffer long-term side effects later in life. The research team was led by University of Buffalo associate professor of pharmaceutical sciences, Javier G. Blanco, PhD.
Blanco and his collegues have been trying to find underlying genetic answers as to why some pediatric cancer survivors treated with anthracylines developed cardiomyopathy, including congestive heart failure, said Science Daily. Anthracyclines—powerful antibiotics like Adriamycin and Daunomycin—are, “effective drugs used to treat a variety of pediatric cancers, they are also used to treat breast cancer and other malignancies in adults,” said Blanco.
“After cancer, survivors can develop cardiac toxicity anywhere from one year to more than 15 years after the initial chemotherapy with anthracyclines. The window separating the effectiveness of these drugs from their toxicity is narrow. The dosage has to be precise to achieve a therapeutic effect without toxicity,” he added, wrote Science Daily. Blanco pointed out that, to make individualized drug therapy, it is important to understand how a patient is genetically coded to respond to a medication once it is in the body and to adjust that drug’s dose accordingly, wrote Science Daily.
Blanco worked with Smita Bhatia, MD, MPH, chair of the Department of Population Sciences at City of Hope National Medical Center in California and senior author of the study. The team reviewed how the drug was identified by enzymes encoded by certain genes, said Science Daily. The enzymes—carbonyl reductases (CBR1 and CBR3)— break down anthracyclines into cardiotoxic alcohol metabolites, said Science Daily.
The study, initiated seven years ago, compared DNA genotypes for 170 childhood cancer survivors diagnosed with anthracycline-related cardiomyopathy. This group, said Science Daily, was compared to a control group of 317 survivors with no heart disease. The team used a “candidate gene approach” and identified a small gene variant linked to cardiotoxicity risks, said Science Daily. “We pinpointed the genetic difference or polymorphism that makes an enzyme work faster or slower in patients,” said Blanco, “slower is better,” he noted, said Science Daily.
The research revealed that cardiomyopathy risks significantly increased in people with two copies of the “G” version of the CBR3 polymorphism when exposed to just low-to-moderate levels of anthracycline. “So far, we are showing an association, not yet causation. Our next step will be to conduct a prospective study” following patients in real time as they are receiving the drug and after,” said Blanco, wrote Science Daily. “Parents must continue to have their children’s health monitored long after the cancer is cured to identify cardiac problems if they develop.”