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Combination of Toxin and Poison May Be Novel Treatment for Leukemia

Johns Hopkins Medicine
Office of Communications and Public Affairs
Media Contact: Vanessa Wasta
410-955-1287
E-mail: wastava@jhmi.edu
March 15, 2004

Combination of Toxin and Poison May Be Novel Treatment for Leukemia

Johns Hopkins Kimmel Cancer Center scientists have discovered why arsenic has long been a successful way to treat certain leukemias, and in the process have shown that a combination of the poison and a second naturally occurring toxin may provide a potent new therapy for them.

The researchers discovered that arsenic, a naturally occurring element, actually activates the same cellular self-destruct mechanism as a compound called bryostatin, a toxin found in coral-like aquatic organisms.  The findings are reported in the March 16 issue of Proceedings of the National Academy of Sciences.

Used for centuries for a variety of medicinal purposes, arsenic was first used as therapy for cancer in post-revolution China and is known to be effective against treatment-resistant acute promyelocytic leukemia (APL), a cancer of the blood and bone marrow characterized by unhealthy myeloid or white blood cells.

The method in which arsenic kills cancer cells, however, was not fully understood until Johns Hopkins scientists used molecular studies to track the poison's target to NADPH oxidase, an oxygen-producing enzyme complex.

In their experiments, the researchers used a low-dose combination of bryostatin and arsenic to kill APL cell lines in the laboratory.

"When normal white blood cells engulf invading bacteria, NADPH oxidase produces a big burst of bad oxygen species which they dump into bacteria to kill it and, in the process, kill themselves," says Chi V. Dang, M.D., Ph.D., vice dean for research and professor of medicine, cell biology, pathology and oncology.  "We found that in APL, arsenic triggers activation of NADPH oxidase and uses this natural bacteria-killing mechanism against the leukemia cells -- in essence, a self-destruct switch."

But arsenic alone is not enough, say the researchers.  "Even with arsenic treatment, much of the NADPH oxidase remains dormant in our system," explains Dang.  However, previous molecular studies showed that NADPH oxidase also is activated by the drug bryostatin, which is currently under clinical investigation for a wide variety of cancers.  In its unengineered form, bryostatin comes from the secretions of a sea organism called a bryozoan that attaches to boat hulls, rocky surfaces, and piers.  "So, we used bryostatin to wake up the rest of it," says Dang.

Doses of the combination arsenic-bryostatin therapy used in the Johns Hopkins research were one tenth of the doses administered in typical
clinical trials testing both drugs individually.  "Arsenic is similar to other chemotherapeutic agents in terms of its potential toxicity, and
there's a trade-off in how much harm you do to normal cells versus cancer cells," says Wen-Chien Chou, M.D., Ph.D., a postdoctoral student at Johns Hopkins and first author of the research.  "Yet, the synergistic effects of combining two drugs that activate the same pathway may allow us avoid toxicity using such low doses."

The researchers will be studying the combination of these drugs in additional cell lines and must test the strategy in animal models before
clinical trials can be conducted in APL.  "There's still a question of whether the leukemic cells die by triggering differentiation rather than the oxygen burst, but either way, we're stopping the cells," says Dang.

APL is a subtype of acute myeloid leukemia, which is the most common form of adult leukemia associated with poor outcome."

The research was funded by the National Cancer Institute, The National Institutes of Health.

In addition to Dang, other participants in this research were Wen-Chien Chou, Chunfa Jie, Andrew Kenedy, Richard Jones, and Michael Trush.

 

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