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Genes delivered by nanotechnology cut lung tumors
Source: (cancerfacts.com)
Tuesday, January 16, 2007
HOUSTON – Jan. 16, 2007 – Using a combination of gene therapy and nanotechnology, scientists have cut the number of human non-small cell lung cancer tumors in mice by 75 percent, a new study shows.
In the study published in the Jan. 15, edition of Cancer Research, the researchers led by Dr. Jack Roth, professor and chair of the M. D. Anderson Department of Thoracic and Cardiovascular Surgery, used nanotechnology to deliver into cancer cells two genes that trigger programmed cell death, which are often shutdown when cells become mutated by cancer.
"In cancer treatment we have combination chemotherapy, and we also combine different modes of therapy - surgery, radiation and chemotherapy," Roth said in a prepared statement. "Now you've got the possibility of combined targeted gene therapy."
Nanotechnology refers to the precise building on a molecule-by-molecule scale of microscopic machines or products. In this study, the researchers used a circular nanoparticle composed of a bit of genetic material, called a plasmid, to transfer two genes into the cancer cell nucleus. These plasmids can then be cloned into large quantities.
One of the transferred genes is p53, a well-known tumor suppressor that works by causing defective cells to commit suicide. The other gene is FUS1, a tumor-suppressor discovered by the research group that is deficient in most human lung cancers. In this case each nanoparticle given intravenously carried one of the two genes, thus delivering a one-two punch to the tumor cells.
In laboratory experiments the researchers showed that the two tumor-suppressing genes reduced cancer separately but had their most powerful effect when administered together. Further analysis showed that the combination achieved greater cell suicide because FUS1 suppresses a gene that expresses a protein known to rapidly degrade p53, says senior author Dr. Lin Ji, associate professor of thoracic and cardiovascular surgery M. D. Anderson.
Using the nanoparticle delivery system, which the researchers have used for years, they wrapped the nanoparticles tightly in a form of cholesterol in order to "sneak" the therapeutic genes past the body's defense mechanisms. The nanoparticles injected into a vein accumulate mainly in the lungs, particularly in the tumors, Ji says. The positively charged nanoparticles are delivered to the negatively charged cancer cell membrane and taken into the cell, where the genes repeatedly express either p53 or FUS1 tumor-suppressing proteins.
In the mice injected with both nanoparticles the number of tumors per mouse was cut by 75 percent and the weight of tumors was reduced by 80 percent.
Roth expects the research team to advance combination therapies to clinical trials in the coming years, either of genes or of genes with other biologic or chemotherapy agents.
"We certainly hope this approach will be more effective but we also think it's likely to be much less toxic, with fewer side effects, than other types of combined cancer therapy," Roth says. "These genes don't have much effect on normal tissue or normal cells when they are overexpressed (overproduced). It's really just cancer cells where they seem to have their effect. Ultimately, the usefulness of this approach has to be proven in clinical trials."
The FUS1 nanoparticles are being tested alone in a phase 1 safety and dose-escalation clinical trial at M. D. Anderson for patients with advanced non-small cell lung cancer that has spread to other organs. Dr. Charles Lu, associate professor in the M. D. Anderson Department of Thoracic, Head and Neck Medical Oncology, is conducting the clinical trial, which is funded by M. D. Anderson's and the University of Texas-Southwestern's joint National Cancer Institute Specialized Program of Research Excellence (SPORE) in lung cancer.
Research was supported by a National Cancer Institute, U.S. Department of Defense TARGET Lung Cancer Programs grant, W.M. Keck Gene Therapy Career Development grant, M. D. Anderson's Cancer Center Support Grant, and a grant from the Tobacco Settlement Funds appropriated by the Texas Legislature.
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