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Treatment Can Make Cancer Stronger

But New Cancer Treatment 'Revolution' Under Way

HIF: Key to Cancer Treatment Success?

"It's been shown that in a variety of different cancer types, those with most HIF-1 have the worst outcome," Semenza tells WebMD. "The basis for this is the fact that HIF-1 controls the expression of hundreds of genes that play critical roles in cancer biology."

One of the first researchers to start looking for drugs that target HIF-1 is oncologist Giovanni Melillo, MD, of the U.S. National Cancer Institute (NCI). After screening hundreds of compounds for anti-HIF activity, Melillo and colleagues made a surprising discovery: A number of existing cancer chemotherapies turn out to inhibit HIF.

The most potent, Melillo says, is a drug called topotecan, marketed under the brand name Hycamtin. It's already approved by the FDA as a second-line treatment for ovarian and small-cell lung cancers. So why isn't this drug already revolutionizing cancer treatment?

"The key to this treatment is the dose," Melillo tells WebMD. "For chemotherapy, one usually gives the maximum tolerated dose. And the timing is important, because when topotecan is used as chemotherapy one needs to let the patient recover from toxicity. We propose to give lower doses of topotecan daily to achieve this effect on HIF-1 in a nontoxic fashion."

Indeed, in an NCI clinical trial, Melillo and colleagues found that topotecan given this way does not have the toxic effects seen when the drug is used in massive doses as a chemotherapy.

But if cancer researchers have learned one thing, it is that no single type of treatment is going to cure cancer.

"Successful treatment of tuberculosis requires the administration of three antibiotics; successful treatment of AIDS requires the administration of three antiviral agents," Semenza recently wrote. "It is not reasonable to expect that the successful treatment of cancer can be accomplished reliably with any fewer than three anticancer agents."

Semenza, Dewhirst, and Melillo agree that HIF-1 inhibitors will have major effects only when combined with other agents.

Dewhirst proposes using such inhibitors along with radiation and chemotherapy. Melillo and Semenza are excited about using the drugs with angiogenesis inhibitors, such as Avastin, which prevent tumors from growing new blood vessels.

Melillo's team is planning a clinical trial testing Avastin in combination with topotecan. And Dewhirst and colleagues have just completed an early safety study of another HIF-1 inhibitor, ENMD-1198 from EntreMed Inc. (Dewhirst has no financial interest in the company).

"HIF-1 inhibition is a very exciting opportunity for cancer treatment," Dewhirst says.


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