Leaky blood vessels in bone marrow can lead to chemotherapy failure in acute myeloid leukemia.
Experimental drugs used to treat heart and blood vessel problems may be able to bolster the effects of chemotherapy for acute myeloid leukemia (AML), a new study published by Cancer Cell suggests.
AML causes bone marrow to emit blood, making it difficult for chemotherapy to attack cancer cells. Drugs that inhibited the bone marrow leaks were found to improve the efficacy of chemotherapy in both mice and human tissue.
The authors believe that these heart drugs may be used as a novel treatment for AML.
"We found that the cancer was damaging the walls of blood vessels responsible for delivering oxygen, nutrients, and chemotherapy. When we used drugs to stop the leaks in mice, we were able to kill the cancer using conventional chemotherapy," said first author Diana Passaro, PhD.
Since the drugs are currently in clinical trials, an additional indication for AML—if proven in further studies—would be less arduous than a normal new drug approval.
Although AML is rare, it is particularly aggressive and affects older individuals. It is likely that the prevalence of AML will increase as the population ages. Less than one-quarter of AML patients survive 5 years after diagnosis due to resistance and relapse.
The investigators injected mice with bone marrow from AML patients and compared this with the bone marrow of healthy mice. They found that the fluorescent-marked dyes leaked out of the bone marrow blood vessels in AML mice but not in healthy animals, according to the study.
The authors then analyzed why the bone marrow became leaky and discovered that the cells lining the blood vessels were starved of oxygen compared with healthy vessels. This likely was caused by AML cells using a majority of the oxygen, which caused an increase in nitric oxide (NO) production, according to the authors.
Since NO is a known muscle relaxant, the authors hypothesized that it may result in bone marrow leakage by increasing the space between cells.
"When the vessels are leaky, bone marrow blood flow becomes irregular and leukemia cells can easily find places to hide and escape chemotherapy drugs," Dr Passaro said. "Leaky vessels also prevent oxygen reaching parts of the bone marrow, which contributes to more NO production and leakiness."
Inhibiting NO was observed to restore blood vessel function and prevent any leaks. Notably, mice administered NO inhibitors plus chemotherapy had slower disease progression and stayed in remission longer than mice given chemotherapy alone, according to the study.
"By restoring normal blood flow with NO blockers, we ensure that chemotherapy actually reaches the leukemia cells, so that therapy works properly,” Dr Passaro said.
The investigators also found that NO inhibitors increased the number of stem cells in the bone marrow, which may create more optimal outcomes due to increased numbers of healthy cells.
Bone marrow biopsies from AML patients were found to have higher NO levels compared with healthy samples. Samples with high NO levels were found to have increased rates of chemotherapy failure, suggesting that lowering NO levels may improve outcomes, according to the study.
"Our findings suggest that it might be possible to predict how well people with AML will respond to chemotherapy," said senior author Dominique Bonnet, PhD. "We've uncovered a biological marker for this type of leukemia as well as a possible drug target. The next step will be clinical trials to see if NO blockers can help AML patients as much as our pre-clinical experiments suggest."