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    Treatment Can Make Cancer Stronger

    But New Cancer Treatment 'Revolution' Under Way

    A 'New' Theory of Cancer continued...

    Each of these things makes cancer worse:

    • New blood vessels let the tumor grow larger.
    • Cells that don't use oxygen are much less sensitive to chemotherapy and radiation.
    • Cells resistant to bursts of oxygen (oxidative stress) also are resistant to some of the ways the body gets rid of cancer cells.
    • Cells that wander spread cancer to distant parts of the body.

    Johns Hopkins researcher Gregg Semenza, MD, PhD, calls this discovery one of the four "major conceptual advances over the last century which have the potential to revolutionize cancer therapy."

    Part of that revolution has been Semenza's discovery of HIF-1. HIF-1 is the signal that transforms a cell from an oxygen-using cell to an anaerobic cell.

    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.

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