Anil Sood, M.D., professor in the M. D. Anderson Departments of Gynecologic Oncology and Cancer Biology. Photo Credit: M. D. Anderson, HoustonFebruary 27, 2008 (Sawf News) - The protein interleukin-8 (IL-8) that stimulates blood vessel growth worsens ovarian cancer, but its production can be stifled by a tiny bit of RNA wrapped in a fatty nanoparticle, said Anil Sood, M.D., professor in the M. D. Anderson Departments of Gynecologic Oncology and Cancer Biology.
The research reports that high IL-8 expression in tumors is associated with advanced tumor stage and earlier death for ovarian cancer patients. Lab experiments and research in a mouse model show that short interfering RNA (siRNA) can cut IL-8 expression, reducing tumor size by attacking its blood supply.
Interleukin-8 is overexpressed in many types of cancer and has previously been shown to promote tumor growth, new blood vessel growth known as angiogenesis, and metastasis, the spread of cancer to other organs. "In the long run, this research will have applications in other cancers as well," Sood said.
To examine IL-8's role in ovarian cancer, the researchers analyzed tumors from 102 patients diagnosed and treated between 1988 and 2006 at M. D. Anderson and the University of Iowa. Of those, 43 had tumors with high levels of IL-8 and 59 had low levels. The median survival of those with high IL-8 tumors was 1.62 years, compared with 3.79 years for those with low expression of the protein.
Genes transcribe single strands of RNA that in turn are "read" by ribosomes to produce proteins. siRNAs are short, double-stranded bits of RNA capable of halting that process. The team confirmed in a lab experiment that a specific siRNA silences IL-8 and then tested it against two lines of ovarian cancer in a mouse model.
Sood, Gabriel Lopez-Berestein, M.D., professor in M. D. Anderson's Department of Experimental Therapeutics, and colleagues are building an arsenal of siRNAs capable of silencing genes that produce cancer-promoting proteins. They packaged siRNA that stymies IL-8 into a small ball of fat known as a liposome, a combination they developed to overcome a problem - siRNA is hard to deliver to tumors.
Tumors shrank by a median of 32 percent and 52 percent in the two cancer lines among mice that received injections of the IL-8 siRNA liposome compared to those receiving control siRNA or empty liposomes.
Mice that got both the IL-8 siRNA plus the taxane-based chemotherapy drug docetaxel had median tumor weight reduction of 90 percent and 98 percent in the two cell lines. Mice with control siRNA plus docetaxel saw reductions of 67 and 84 percent.
Finally, they tested the approach in mice with an ovarian cancer cell line known to be resistant to taxane-based drugs such as docetaxel. IL-8 siRNA alone reduced the size of these tumors by 47 percent, and when combined with docetaxel reduced tumor size by 77 percent, suggesting that the combination re-sensitizes a resistant tumor to taxanes.
"These are encouraging results. We want to move one of our siRNA agents into the clinic to test its potential for therapy," Sood said, "and then in the longer term, we'll consider moving additional siRNA agents into the clinical arena."
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