Cancer Treatments on the "Cutting Edge"

Cancer researchers are striving to improve the options available to patients; a point made clear by ideas presented at the 1998 American Cancer Society Science Writers Seminar. Among the experimental strategies: 

• a gel that holds toxic chemotherapy drugs inside tumors, 
• an enzyme-based drug that singles out cancer cells, (this drug became Gleevec, a revolutionary leukemia drug)
• a DNA vaccine against a cancer gene.

In most cases, chemotherapy drugs circulate throughout the body, so the doses that can be given safely are usually limited by side-effects. For example, many chemotherapy drugs attack cells that are rapidly dividing; unfortunately, that means they often damage bone marrow cells, which, like cancer cells, grow rapidly. 

The chemotherapy gel being worked on by Dr. Harinder Garewal and colleagues at the Arizona Cancer Center is based on a simple desire: to concentrate the killing power of chemotherapy drugs on tumors, while sparing normal tissues from their toxic onslaught. In the first phase of tests in cancer patients, researchers used a mixture of cisplatin and epinephrine, proven treatments for certain cancers. But in the gel experiment, doctors managed to increase the concentration of chemotherapy drug inside the tumor to between 10 and 100 times the level of standard treatment. Despite that intense concentration of drug attacking the cancer, the total dose used was a small fraction of standard treatment: from 5 to 20 mg, compared to 160 to 220 mg for standard chemotherapy; so the patient's normal tissues were subjected to very little of the toxic drug. 

More importantly, researchers say the tactic worked. In one trial involving 82 patients with advanced metastatic cancers, 39 percent had complete responses to the treatment, while an additional 11 percent had partial responses. "It should be emphasized that in such a... group of tumors, it is unusual to encounter even one or two responses," says Dr. Garewal. "The response in the lesions is durable. It won't come back." He adds that overall the treatment was well-tolerated. 

However, Dr. Garewal emphasizes that while the chemotherapy gel can destroy individual tumors, the patients with metastatic disease were not cured, because new tumors eventually appeared that could not be treated with gel injections. In particular, the strategy may not work for brain tumors, because it causes swelling which could be dangerous within the confines of the skull. 

"It's a very clever idea," says Frank McCormick, PhD, director of the the University of California-San Francisco Cancer Center. He points out that, even if it is not curative, the treatment could offer real benefits to patients with head and neck cancers by shrinking tumors that are obstructing their airways. 

The gel is made from cow collagen, similar to material used in cosmetic injections, but it has been re-engineered in order to produce some special properties. "It's based on collagen," says Dr. Garewal, "but the final product is quite different. It took a lot of development work." The most important feature is the gel's response to body heat. While most material become softer at higher temperatures, this gel, which is a liquid at room temperature, solidifies at body temperature. That property means it can be injected through a syringe directly into a tumor, where is hardens, trapping the drug within the cancer growth. After the drug has done its job, the collagen eventually dissolves. 

The researchers are now pursuing a second phase of trials to test the effectiveness of the gel. One group of patients has recurrent head and neck cancer. A separate test is underway on patients with liver tumors. In order to get objective results, neither the researchers nor the patients will know which patients are receiving gel injections containing active chemotherapy and which are getting a placebo. 

DNA Vaccines

A new type of vaccine could also offer a way to use unique features of cancer cells to focus an attack. Dr. Hildegund Ertl of the Wistar Institute in Philadelphia is studying vaccines made from the genetic material, the DNA, of cancers. She is concentrating on a gene known as p53, which is mutated in many types of cancer. 

Dr. Ertl says the surfaces of many cancer cells are covered with abnormal amounts of the protein produced by p53, while normal cell surfaces exhibit very little p53. The researchers attached the p53 gene to an altered form of a virus to make what is known as a "DNA vaccine." The idea is that when the vaccine is injected into the body, immune cells will recognize the virus and the attached p53 gene as invaders and mount a counter-attack. The hope is that the immune response would be concentrated on the cancer cells with high levels of p53 on their surfaces. 

The technique has protected some laboratory animals against tumor cells. A combination of the DNA vaccine with other substances that boost the immune system was able to shrink some established tumors in test animals. 

However, Dr. Ertl points out that the form of the vaccine tested so far is not 100 effective, even in laboratory animals, so several years of work remains before testing with people can even begin. 

Enzyme Target

The American Cancer Society seminar also heard of research at the Oregon Health Sciences University, where researchers are hoping to help some leukemia patients by exploiting a unique feature of their blood cancer cells. 

The target of this work is a protein molecule called Bcr-Abl. It is an abnormal molecule related to enzymes that control cell growth. The researchers were attracted to Bcr-Abl because it appears only in chronic myelogenous leukemia, known as CML; normal cells don't have any Bcr-Abl. 

The researchers developed a drug that would block the Bcr-Abl enzyme, while not affecting any normal enzymes. "Our studies demonstrate that this compound kills cells that contain Bcr-Abl, but does not kill normal cells," says Dr. Brian Druker of OHSU. Tests in patients with CML are scheduled to begin this year at OHSU, the University of California at Los Angeles, and M.D. Anderson Cancer Center in Houston, Texas. 

New CML treatments are urgently needed; standard therapies cure only one patient in five. But the ultimate promise of this work is not limited to CML. Basic research is rapidly uncovering molecular abnormalities that are unique to other cancers. In each case, the researchers say, it may be theoretically possible to identify targets for drugs that could kill cancer cells, while leaving normal cells unaffected. However, they stress that this line of research has yet to prove itself in tests on patients.