Researchers have found in a preclinical trail, that siRNA packed as a tiny sphere can shrink ovarian cancer.//
Researchers from the University of Texas M. D. Anderson Cancer Centre had reported in the August 15th edition of Clinical Cancer Research, that siRNA that are wrapped up in a tiny sphere infiltrate deeply into ovarian cancer tumour cells, which could thereby oppress the troublesome protein and drastically reducing the size of tumours.
Anil Sood, M.D., associate professor in the Departments of Gynaecologic Oncology and Cancer Biology at M. D. Anderson, and the senior author explained that their experiment that was conducted on a mouse shows the effective delivery system for the short interfering RNA, (siRNA) in attacking the cancer cells.
Short interfering RNA is a great technology we can use to silence genes, shutting down production of harmful proteins, Sood says. 'It works well in the lab, but the question has been how to get it into tumours.' Short pieces of RNA don't make it to a tumour without being injected directly, and injection methods used in the lab are not practical for clinical use.
The research team took siRNA that targets a protein that helps ovarian cancer cells survive and spread and rolled it into a liposome -- a lipid ball so small that its dimensions are measured in nanometers (billionths of a meter).
Getting the siRNA inside tumour cells is important, Sood said, because the targeted protein, focal adhesion kinase (FAK), is inside the cell, rather than on the cell surface where most proteins targeted by cancer drugs are found. 'Targets like FAK, which are difficult to target with a drug, can be attacked with this liposomal siRNA approach, which penetrates deeply into the tumour,' Sood said.
Mice infected with three human ovarian cancer cell lines derived from women with advanced cancer were treated for 3-5 weeks. They received liposomes that contained either the FAK
siRNA, a control siRNA, or were empty. Some mice received siRNA liposomes plus the chemotherapy docetaxel.
Mice receiving the FAK-silencing liposome had reductions in mean tumour weight ranging from 44 to 72 percent compared with mice in the control groups. Combining the FAK-silencing liposome with docetaxel boosted tumour weight reduction to the 94-98 percent range.
These results also held up in experiments with ovarian cancer cell lines resistant to docetaxel and to the chemotherapy drug cisplatin.
The FAK-silencing liposome and the liposome with chemotherapy also reduced the incidence of cancer by between 20 and 50 percent in all tested cancer lines.
In addition to its anti-tumour effect, the researchers found that the therapeutic liposome attacked the tumour's blood supply, especially when combined with chemotherapy. By inducing cell suicide (apoptosis) among blood vessel cells, the treatment steeply reduced the number of small blood vessels feeding the tumour, cut the percentage of proliferating tumour cells and increased cell suicide among cancer cells.
Sood and Professor of Molecular Therapeutics Gabriel Lopez-Berestein, M.D., an expert in liposomal therapeutics, cite at least two factors for the success of the anti-FAK liposome.
'This particle is so small, it has no problem getting through the tumour's vasculature and into the tumour,' Lopez-Bernstein says. The FAK-targeting liposome ranges between 65 and 125 nanometers in diameter. Blood vessels that serve tumours are more porous than normal blood vessels, with pores of 100 to 780 nanometers wide. Normal blood vessel pores are 2 nanometers or less in diameter.
Second, the liposome -- a commercially available version known as DOPC -- has no electrical charge. Its neutrality provides an advantage over positively or negatively charged liposome's when it comes to binding with and penetrating cells.
The next step for
the FAK siRNA-DOPC liposome is toxicity testing. 'So far it appears to be very well-tolerated,' Sood says. 'We hope to develop this approach for clinical use in the future.'
In addition to ovarian cancer, FAK is over expressed in colon, breast, thyroid, and head and neck cancers.
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