This report originally appeard on the Sapient Health Network web site, which later became WebMD.
"Suicide Gene Therapy" Shows Promise for Prostate Cancer
Exclusive Report from the 1998 ASCO Meeting
July 1, 1998 --
Researchers are trying to trick prostate cancer cells into committing suicide. The key is a type of gene therapy that can make tumors sensitive to a drug, ganciclovir, that normally attack herpes viruses.
At the American Society of Clinical Oncology annual meeting, Dr. Peter Scardino of the Baylor College of Medicine in Houston, Texas reported early results of this gene therapy on 18 men who had locally-recurrent prostate cancer, after originally being treated with radiation. "We completed the trial showing this could be given to patients with prostate cancer safely. The side effects were minimal and dose-related. And there was evidence of activity in 3 of the 18 patients with prostate cancer."
Dr. Scardino says this trial is the first to show activity in prostate cancer patients using this form of gene therapy. Other researchers are testing different approaches that either attempt to correct defective genes that cause or promote cancer, or use genetics to boost immune system defenses against cancer.
The three patients who responded had a greater than 50 percent reduction in PSA. One patient had a biopsy after treatment that was negative. The researchers say that overall toxicity was mild. Side effects rose with higher doses of therapy, but only one patient, who received the highest dose, had serious problems. He had a drop in blood cell counts and abnormal liver functions, which were treatable.
Further tests are planned in order determine the most effective method of applying this type of gene therapy to recurrent prostate cancer.
This so-called "suicide gene therapy" has been used in a number of other cancers that resist standard treatment, including ovarian cancer and certain brain tumors. Here's how it works:
* Scientists add a gene taken from the herpes simplex virus to another virus that has been altered so that it does not spread or cause disease.
* The altered virus is injected directly into the tumor, where it acts like a delivery truck, infecting the tumor cells and "dropping off" its herpes gene cargo. The delivery virus is more likely to be picked up by rapidly growing cells, so it tends to concentrate in tumor cells, rather than normal cells.
* The herpes gene instructs the cancer cells to begin producing a chemical called thymidine kinase, which is not found in normal human cells.
* The patient is then given a drug called ganciclovir. This anti-herpes drug is relatively non-toxic to most cells.
* When ganciclovir enters a cancer cell that has been infected with the herpes gene, the thymidine kinase now being produced in the cell metabolizes the drug into a toxic triphosphate form; thus the cell makes the poison that then can kill it.
Since ganciclovir is toxic only after it is metabolized by thymidine kinase, the drug's killing effect is concentrated within the tumors altered by gene therapy, thus minimizing any side effects.
A somewhat surprising feature of this type of therapy is that it can shrink tumors even though only a relatively small percentage of cancer cells are actually infected with the "suicide gene." The extra killing power comes from what is known as the "bystander effect," in which the death of one tumor cell can lead to the death of nearby tumor cells as well. Even when only 10 to 15 percent of tumor cells take up the new gene, as many as 90 to 95 percent of tumor cells may die.
Researchers have several ideas about how this bystander effect may work. Some of the toxic metabolites of ganciclovir may cross over from infected cells to uninfected cells. Live tumor cells may absorb pieces of dead tumor cells. Or perhaps something in the process of tumor cell death triggers a stronger immune system reaction against remaining tumor cells. While the bystander effect rarely eliminates all cancer cells, researchers say repeated gene therapy treatments have eliminated tumors in some laboratory animal experiments.
The researchers point out that this "suicide gene therapy" can be used only against localized tumors, since the virus carrying the herpes gene must be injected directly into the tumor; so it is unlikely to be effective against prostate cancer that has already spread. Nevertheless, Dr. Scardino believes the treatment may someday offer a way to help prevent the spread of prostate cancer in the first place. "It could be used prior to surgery in men who are at high risk of having spread," he suggests, "because in laboratory animals, when you inject into the primary tumor, it actually suppresses or eliminates the development of metastases. So it could be used in combination with surgery or radiotherapy as well."
But that sort of exploration will have to wait while researchers further test the safety and effectiveness of the basic approach in men with recurrent prostate cancer. Dr. Scardino predicts that work will take five to eight years; and he cautions patients not to expect this sort of gene therapy to become available quickly.
"We are in the very earliest stages," Dr. Scardino says. "To the best of my knowledge, this is the only trial that has actually shown any real sign of activity. Several other forms of gene therapy for prostate cancer have shown safety, and show a lot of promise; but I don't think there's been any others that have even shown activity. And this trial obviously is very preliminary."
Variations on the approach are also under study. For instance, instead of using a herpes gene to make tumor cells sensitive to ganciclovir, some researchers are giving tumor cells a gene that makes them sensitive to the drug 5-fluorocytosine. Researchers in Michigan are even testing a therapy that would use both types of genes in the same injection. In their experiments, gene activation is triggered by using a probe to heat the tumor. In this way, even if normal cells outside of the tumor were exposed to the injected genes, without the extra heating step, the genes would remain inactive.
Yet the basic idea of these experiments is the same: harnessing the power of genetics to create weaknesses in cancer cells, so that doctors can use drugs that will be simultaneously more toxic to tumors, while being relatively easy on patients.
Roth JA, Cristiano RJ; MD Anderson Cancer Center: "Gene therapy for cancer: What have we done and where are we going?" Journal of the National Cancer Institute, Vol. 89(1):21-39, Jan. 1, 1997.
Eastham JA, et al.; Matsunaga-Conte Prostate Cancer Research Center, Houston, TX, USA.; "Prostate cancer gene therapy: herpes simplex virus thymidine kinase gene transduction followed by ganciclovir in mouse and human prostate cancer models;" Human Gene Therapy, March 1, 1996;Vol. 7(4):515-523
Blackburn RV, et al.;Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan 48073-6769, USA; "Adenoviral-mediated transfer of a heat-inducible double suicide gene into prostate carcinoma cells;" Cancer Research, April 1, 1998; Vol. 58(7):1358-1362
Tong XW, et al.; Department of Obstetrics and Gynecology, Baylor College of Medicine Houston, TX 77030, USA; "Improvement of gene therapy for ovarian cancer by using acyclovir instead of ganciclovir in adenovirus mediated thymidine kinase gene therapy;" Anticancer Research, March 1998; Vol. 18(2A):713-718
Source: Exclusive SHN Report
Copyright © 1998 by Sapient Health Network. All rights reserved.
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