The drug R115777 (Zarnestra) (tipifarnib) produced responses that ranged from complete responses to improvement in blood counts in about one-third of 82 patients treated at seven different hospitals in the United States, Canada, and Europe, says the study's lead investigator, Razelle Kurzrock, M.D., a professor in the Department of Experimental Therapeutics at M. D. Anderson Cancer Center.

That level of response, as well as side effects that are well tolerated, can be a boon to the mostly elderly patients who develop the syndrome, Kurzrock says. "It is one more drug that can be tried to help improve blood counts and prevent leukemia development in these patients," she says.

At the time the study began, there was no approved therapy to treat MDS, but recently, the FDA approved use of azacytidine (Vidaza), which is a chemotherapy drug administered subcutaneously. Zarnestra helps about as many patients as Vidaza, "but for diseases like this, you need more than one drug because the syndrome is made up of numerous subtypes," Kurzrock says. "If one drug doesn't help, then the other might; or they could potentially be used together."

Zarnestra belongs to a group of drugs known as farnesyl transferase inhibitors, which block enzymes needed for the activation of cancer-promoting proteins. While the drug was initially believed to act primarily on the ras gene, which is mutated in about 25 percent of MDS patients, recent studies including this one demonstrate that patients whose ras gene is normal can benefit, Kurzrock says. "It has become apparent that Zarnestra regulates other important cancer genes, although we don't know which ones they are."

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ABC transporters are membrane-spanning proteins that export a variety of molecules across cell membranes. Powered by ATP hydrolysis, the 48 different ABC transporters encoded by the human genome play pivotal roles in normal physiology. In melanomas, aberrant ABCB5 transporters may allow cells to resist chemotherapy, even when multiple drugs are used. Chen and colleagues found mRNAs corresponding to two novel isoforms of ABCB5, named ABCB5a and ABCB5b, that were preferentially expressed in 75 percent of the melanomas represented in the National Cancer Institute-60 (NCI-60) panel of cancer cell lines. The first isoform, ABCB5a, comprises only a partial ABC transporter and is probably not functional alone. The other isoform, ABCB5b, is approximately 70 percent similar to the protein encoded by a different gene, ABCB1 (a.k.a. MultiDrug Resistance gene, MDR1), and has a predicted membrane topology similar to the carboxyl terminal half of ABCB1. Neither aberrant ™ isoform was expressed in normal tissues from the liver, spleen, thymus, kidney, heart, lung, colon, small intestines or placenta. However, they are the predominant ABCB5 isoforms expressed in melanoma cells, normal melanocytes and pigment-forming retinal cells, suggesting that ABCB5a/b expression is limited to cells that normally produce pigment.

How would these special versions of ABCB5 lead to multi-drug resistance in melanomas? Chen and Gottesman speculate that normal ABCB5 transporters help cells export cytotoxic compounds currently used as anti-cancer drugs. One or both of the aberrant ABCB5 isoforms are proposed to work in conjunction with other isoforms to enhance drug export and make melanoma cells drug-resistant. Supporting this model, cells that express the ABCB5b isoform have a drug response pattern different from that of ABCB1-expressing cells. These ideas will be tested further. Meanwhile, the discovery that ABCB5a/b isoforms mark ™ most cancerous melanomas provides two molecular markers for the differential diagnosis of melanomas, and might be used to specifically target melanomas in anti-cancer therapy.

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