Researchers at the Johns Hopkins University School of Medicine have discovered how a whole class of commonly used chemotherapy drugs can block cancer growth.
Their findings, reported online this week at the Proceedings of the National Academy of Sciences Early Edition, suggest that a subgroup of cancer patients might particularly benefit from these drugs.
The anthracycline class of chemotherapeutics - doxorubicin (Adriamycin), daunorubicin, epirubicin, idarubicin - have been used for four decades to treat many types of cancer, including leukemia, lymphoma, sarcomas and carcinomas, The standard method of administration had been to use the highest tolerable dose every few weeks to kill all rapidly growing cells by preventing them from accurately copying their genetic material.
"But the late Judah Folkman discovered in 2000 that so-called metronomic treatment, giving patients lower doses of these drugs more frequently, can keep cancer growth at bay by blocking blood vessel formation, but the exact mechanism by which this occurred wasn't known," says Gregg L. Semenza, M.D., Ph.D., director of the vascular program at the Johns Hopkins Institute for Cell Engineering and a member of the McKusick-Nathans Institute of Genetic Medicine. "Now we've shown how it happens and what players are involved, which could help shape future clinical trials for patients with certain types of cancers."
Semenza and his team have long studied how the hypoxia-inducible factor, or HIF-1, protein helps cells survive under low-oxygen conditions. HIF-1 turns on genes that grow new blood vessels to help oxygen-starved cells, like those found in fast-growing solid tumors, survive.
To look for drugs that can prevent new blood vessel growth, the team tested more than 3,000 already FDA-approved drugs in the Johns Hopkins Drug Library for their ability to stop HIF-1 activity. Using modified liver cancer cells growing in low oxygen, the team treated cells with each of the drugs in the library and examined whether the drug could stop HIF-1 from turning on genes.
One drug-daunorubicin-reduced HIF-1's gene-activating ability by more than 99 percent. They tested other members of the anthracycline drug class and found that doxorubicin, epirubicin and idarubicin also blocked HIF-1 activity. But further examination showed that both drug-treated and untreated cells contained similar amounts of HIF-1 protein, leading the researchers to conclude that the drugs are not affecting whether or not HIF-1 is made.