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Science to Practice |
Center for Molecular Imaging Research,
Harvard Medical School,
Massachusetts General Hospital,
185 Cambridge St,
Rm 8226,
Boston, MA 02114,
mahmood@helix.mgh.harvard.edu
SUMMARY
Kim et al have demonstrated in an animal model that focal transgene delivery to hepatic tumors is improved when performed with a clinically used chemoembolization vehicle.
THE SETTING
Cancer treatments often involve a combination of therapies with diverse and complementary mechanisms of action that act synergistically to kill tumors. Interventional radiologists are directly involved in the application of many focally administered treatments, including chemotherapy, embolic therapy, and radiofrequency ablation. The preferential insertion of genes into tumors has undergone increasing evaluation to determine if such techniques can augment the efficacy of more traditional tumoricidal methods. In this issue of Radiology, Kim et al (1) evaluated the ability of transcatheter arterial chemoembolization (TACE) techniques and clinically used agents to improve focal tumor delivery of exogenous genes in an animal model of hepatic carcinoma.
THE SCIENCE
There are more than 1000 clinical gene therapy trials that have been completed or are underway (2). More than half of these trials focus on enhancing cancer therapy. One approach involves preferential tumor expression of the commonly used suicide gene, herpes simplex virus-1 thymidine kinase (HSV-1-tk). After there is focal expression of HSV-1-tk, systemic administration of the approved antiviral drug ganciclovir preferentially kills the transfected cells. Because positron emission tomography (PET) imagable analogs (such as 2'-deoxy-2'-fluoro-ß-D-arabinofuranosyl-5-iodouracil) exist, it is possible to image the location and extent of transgene expression after vector delivery in patients with gliomas prior to treatment with ganciclovir (3). Other gene therapy approaches, such as focal expression of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), synergistically enhance the proapoptotic effects of chemotherapy.
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In their study, Kim et al (1) used the preferential arterial supply of hepatic tumors to their advantage for delivering a marker gene. Importantly, they demonstrated that they could overcome the low efficiency of delivery in their nonviral system by using a method that is already used in clinical practice to focally administer and image chemoembolic therapy to hepatic tumors. The authors systematically showed that both the lipophilic and hydrophilic components of the mixture were needed for optimal transgene expression in the tumors and that very little expression was seen outside the tumor, including in the ipsilateral hepatic lobe.
THE PRACTICE
Clinical use:
The use of chemoembolization for hepatocellular carcinoma has had mixed results clinically but may show a benefit in certain groups (5,6). Improvement in the efficacy of focal treatment by adding exogenous genes, such as HSV-1-tk or TRAIL, may be possible. Importantly, all of the components, including the typical therapeutic transgenes, chemotherapeutics, and iodinized oil emulsion, have been previously used in humans. Interventional radiologists performing such chemoembolization procedures will use the same method as TACE, except that the exogenous DNA and a stabilizing agent will be added to the mixture prior to injection. In addition to standard anatomic follow-up imaging to assess tumor shrinkage, there may be earlier molecular imaging (with either PET or magnetic resonance imaging) to assess the location and extent of transgene expression (3,7).
Future opportunities and challenges:
The work presented by Kim et al demonstrates the improved delivery of transgenes to hepatic tumors when combined with a clinically used vehicle for chemoembolization. The next step prior to human use is to show in animal models that there is a benefit of adding a focal gene therapy component compared with the standard combinations used today in TACE. Additional evaluation to see how long the gene expression lasts would be useful to optimize the timing of administration of drugs for which tumoricidal efficacy may be enhanced by the transgenes. Finally, showing that the method works in the setting of cirrhosis is important because many of the patients with hepatocellular carcinoma have cirrhosis. Radiologists will have a key role in the delivery and evaluation of such therapies as they are brought into practice.
FOOTNOTES
See also the article by Kim et al in this issue.
References
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