Non-Technical Abstract 
Intrathecal Gene Therapy for the Treatment of Leptomeningeal Carcinomatosis 
Non-technical Abstract 
Meningeal carcinomatosis is a complication of systemic cancer where malignant tumor 
cells seed the coverings of the brain and spinal cord (leptomeninges). The infiltrating tumor 
occurs in 5% to 20% of all cancer patients, and most adult cases are due to breast or lung 
cancer. Patients with leptomeningeal carcinomatosis present with a variety of neurological 
symptoms corresponding to involvement of cranial and spinal nerves, and infiltration into 
brain and spinal cord tissues. The prognosis is extremely poor. When maximal therapy is 
tolerated (intrathecal chemotherapy and whole-brain irradiation) mean survival is limited to 6- 
7 months and fewer than 15% of the patients are alive at one year. In an attempt to improve 
this grim prognosis of patients with leptomeningeal carcinomatosis, we have developed a 
novel approach for the treatment of this disease. This approach makes use of recombinant 
DNA technology to make the tumor cells sensitive to an antiviral drug called ganciclovir 
(GCV). Sensitivity to the drug is achieved by transferring a foreign gene into the malignant 
cells. This gene is the thymidine kinase gene from the herpes simplex virus. Cells that produce 
mouse viruses, which had been genetically engineered to contain the thymidine kinase gene, 
are injected into the subarachnoid space (intrathecal space; the space that is filled with 
cerebrospinal fluid and is in contact with the tumor cells in the leptomeninges). The viruses 
transfer the gene into the tumor cells and 7 days later the patient is treated with GCV, which 
leads to death of the tumor cells. Since the thymidine kinase enzyme which is normally 
present in mammalian cells has very low affinity for GCV, systemic toxicity related to this 
mechanism is not expected. 
The proposed clinical trial will evaluate the distribution of retroviral vectors in the 
subarachnoid space, assess the safety of this approach, and evaluate its potential antitumor 
efficacy. As the study progresses, increasing numbers of producer cells will be injected into 
the ventricular system (cerebrospinal fluid-filled cavities in the brain) and the spinal 
subarachnoid space. Indications of antitumor efficacy will include monitoring of clinical 
symptoms, craniospinal MRI scans, and CSF analysis for the presence of tumor cells and 
tumor markers. A total of 20 patients will be enrolled in the various phases of the study. 
This is the first clinical attempt to treat meningeal carcinomatosis by in vivo , 
intrathecal, genetic manipulation of the tumor's genome. 
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Recombinant DNA Research, Volume 18 
