Hope For Brain Cancer

By Michael E. Hall, R.N.

Are you hearing a dog barking, turky gobbling, or some other disturbing sounds? You may not be getting senile or schizophrenic. Glioblastomas kill by wreaking havoc on target areas in the brain, not by spraeding throughout the body like other cancers. Glioblastomas grow very fast, some doubling in size every ten days, cutting off the blood supply to itself and an area of the brain leaving an area of dead tissue. Often the location of the tumor is in a part of the brain thought to be involved in our ability to process speech, or remmember voices, songs and other familiar sounds. Surgery and radiation; has in the past, been the standard treatment, now.

An experimental treatment called GLI-328, which is now being tested in many hospitals in the U.S. GLI-328 is neither radiation nor chemotherapy; it is a form of gene therapy, one that may offer victims of glioblastomas a chance to beat the odds.

As much of the tumor as possible is removed. Then, if the diagnosis of glioblastoma is confirmed, a doctor will implant "suicide" cells into the remaining cancer cells to get them to self destruct. Specifically, he will inject mouse skin cells carrying a genetically altered mouse leukemia virus into that particular brain section. The mouse virus contains a gene from the herpes simplex virus. The mouse virus contains the gene from the same virus that causes cold sores, called herpes thymidine kinase-1, or the herpes TK gene. Its manufacturer, Genetic Therapy, Inc., has removed other bits of DNA to cripple the virus, so that it can infect but not reproduce in human cells. In particular, the virus can infect only deviding cells, which means that only brain cells infected with cancer will be atacked, because normal brain cells do not devide. Once infected by the virus, the tumor cells will produce thymidine kinase, making them vunerable to antiviral drug ganciclovir.

Originally the idea was not considered a treatment but a self-destruct mechanism for the first gene therapy experiment. The main concern for use of the mouse leukemia virus was that if you inserted it into the wrong place, it could cause the cells to become cancerous. A self destruct mechanism was then build into the virus. If the worse happened, the plug could be pulled and kill the cells.

In mice, GLI-328 completely kills tumors, without side effects. But while the results of the human trials conducted so far are intriguing, they are also controversial. The Institute of Neurolopgical Disorders and Stroke in Betjhesda, Maryland conducted a pilot study with their cohorts on ten patients who had undergone surgery for glioblastomas and whose tumors had come back. These patients recieved no repeat surgery to remove the growth. Instead the virus was delivered to the tumor site through a thin tube called a cannula, guided by CT-scan images. The patients then recieved follow-up treatments with ganciclovir.

In this small study GLI-328 was safe and effective in some cases, producing decreases in tumor size by 50 percent or more of the ten patients. The gene therapy helped, but, not enough to produce any impact on survival. Because the delivery system limited the therapy to an area just a few cell layer deep, only a very small portion of the tumors responded. And while the therapy reduced parts of the tumors, distant portions progressed very rapidly.

However, a new improved clone of the herpes TK virus was introduced. This study contained 31 patients with recurrent glioblastomas. They underwhent surgery to remove as much of the tumor as possible, then recieved the injections of GLI-328... Results of this trial was also cotroversial. The average survival of the 31 patients was seven months, which isn't an improvement over repeat surgery.

Is the gene therapy helping these patients beat impossible odds? A study in progress in St. Louis and elswhere is trying to, answer that question. 250 patients in ten countries are recieving treatment with surgery, radiation, and gene therapy, or surgery and radiation alone. Unlike those patients in earlier trials, these enrolled in the current study are recieving gene therapy at the time of their initial surgery, not at recurrence. They will be evaluated to see if the gene therapy reduces the time to recurrence, or increases survival compared to standard therapy. This is the first time any gene therapy has been evaluated in a large, randomized trial. If therapy with the herpes TK gene shows a benifit, it could be approved for widespread use as early as the year 2000.

"The gene therapy approach is very exciting because it bypasses the natural biology of these tumor cells, which are very difficult to understand and treat," remarks neuro-onocologist Michael Prado, one of the doctors who tested GLI-328. "It allows you to create a tumor cell that's the way you want it to be...Killable."


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