The common cold virus can fell even the hardiest person -- and it may have the same debilitating effect on cancer cells. If so, interventional radiologists would be the ideal specialists to infect patients with gene-altering viruses for their own good, according to a Stanford University professor.
"What is the role of the interventional radiologist in genetic therapy? Most radiologists tend to tune out when I say that. They may think 'I'm not a microbiologist, I'm not a biochemist, I don't have to learn this stuff,' said Dr. Daniel Sze, speaking June 25 at "State-of-the-Art Interventional Radiology," a conference co-hosted by Osaka University and Stanford.
But well-established interventional radiology techniques could play a crucial role in the targeted delivery of gene therapeutics that would maximize uptake in the targeted cells, and minimize uptake in healthy organs.
"Despite not being biochemists or molecular biologists, we need to be aware of what's going on in the field," said Sze, an assistant professor of radiology.
Sze reviewed various strategies that are in use or under investigation, beginning with regional chemotherapy, which has become a standard of care for nonresectable hepatocellular carcinoma and other hypervascular metastases in the liver. However, "one of the problems with chemoembolization and chemoinfusion, as it stands right now, is that the chemotherapeutics [can only be administered] through a vein," Sze said.
Two drawbacks of this are the possibility of incomplete uptake in the liver and the tumor, along with systemic exposure and toxicity due to high dosing. Also problematic is the nontargeted, intravenous release of adenoviruses that carry gene-altering materials.
"If I give a patient the adenovirus intravenously and then search for where the virus went, almost all of it is sequestered by the reticular endothelial system. It does not actually get into the tumor or the target cells. The rate of transfection in target cells is determined by the route of administration. There's a potential role for embolization and balloon occlusion to trap these viruses where we want them," Sze said.
To that end, several clinical trials are in the works that use tumor suppressor genes, or anti-oncogenes, to destroy cancer cells. The most common tumor suppressor is p53, a version of which is the subject of a clinical trial by Onyx Pharmaceuticals of Richmond, CA, Sze said.
"P53 basically polices the DNA of the cell. If p53 detects that there's any abnormal DNA, then it shuts down DNA synthesis. If it's a small abnormality, p53 will shut down the cell until the cell can repair the DNA and go on to live. If there's too much damage, it goes into apoptosis, or programmed cell death. Two-thirds of cancer cells have defective p53," he explained.
Onyx-015 is designed to exploit that deficiency by using the adenovirus to selectively kill tumor cells. The modified virus has undergone ten phase I and phase II studies in patients with several cancer types, including pancreatic and liver.
Patients were given between 107 and 1011 plaque-forming units of the adenovirus (one plaque-forming unit is equal to one live viral particle) in four infusions over a two-month period. In one patient, a number of hypovascular metasases in the liver had disappeared after 60 days of treatment.
"Unfortunately, this patient developed pulmonary metastases. Remember that we are delivering this virus only to the hepatic artery, which means only the liver is being treated," Sze said.
Still, regional targeted therapy has several advantages, including the ability to deliver a high concentration of chemotherapeutic agents, but avoid the risk of toxic systemic exposure, Sze said. The development of new agents that are better suited for intra-arterial administration will make interventional radiologists uniquely qualified to deliver these agents.
"The techniques used to deliver these viruses are ones with which most interventional radiologists are already very familiar and skilled. As our understanding of the differences between chemotherapy and gene therapy develop, I would expect these techniques to be modified and tailored accordingly," he said.
By Shalmali Pal
AuntMinnie.com staff writer
July 5, 2000
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