CURING LUNG CANCER

One of the great tragedies of this century has been the widespread addiction of large numbers of people to tobacco. An enormously profitable commercial enterprise, the production and marketing of cigarettes now affects a significant fraction of all the people on the planet. Many cigarette smokers are now dying of lung cancer, so it is with real excitement that researchers are now pursuing investigations that offer real hope of curing this deadly disease. For decades it has been clear that cigarette smoking is both habit-forming and somehow linked to lung cancer, but the exact way in which tobacco and lung cancer are linked has evaded researchers. In the last year, however, scientists have uncovered the link. It turns out that tobacco smoke contains a chemical called benzo (a) pyrene which disrupts a key element in the body_s normal defense against cancer. In studying how this tobacco chemical produces cancer, researchers have stumbled across an opportunity to cure it.

TUMOR SUPPRESSOR GENES
The cells of your body guard against cancer in a variety of ways scientists are only beginning to understand. A key element in these defenses are so-called tumor suppressors, proteins which actively prevent tumors from forming. Two of the most important are named Rb and p53.

Rb. Rb (named after retinoblastoma, the rare eye cancer in which it was first discovered) acts as a break on cell division, attaching itself to the machinery the cell uses to replicate their DNA, and preventing it from doing so. When the cell wants to divide, a growth signal molecule ties up Rb so that it is not available to act as a brake on the division process. If the gene which produces Rb is disabled, there are no breaks to prevent the cell from replicating its DNA and dividing. The control switch is locked in the _ON_ position.

p53. p53, the tumor suppressor protein sometimes called the _Guardian Angel_ of the cell, inspects the DNA to ensure it is ready to divide. When p53 detects damaged or foreign DNA, it stops cell division and activates the cell_s DNA repair systems. If the damage doesn_t get repaired in a reasonable time, p53 pulls the plug, triggering events that kill the cell. In this way, mutations such as those that cause cancer are either repaired or the cells containing them eliminated. If the gene that produces p53 is itself destroyed by mutation, future damage accumulates unrepaired. Among this damage are mutations that lead to cancer, mutations that would have been repaired by healthy p53. 50% of all cancers have a disabled p53 gene.

Cigarettes cause lung cancer because they damage these tumor suppressor genes. Fully 70%-80% of lung cancers, for example, have a mutant inactive p53 gene_the chemical benzo (a) pyrene in cigarette smoke is a potent mutagen of p53.

USING A VIRUS TO CURE CANCER
In 1977, virologists discovered that adenovirus (responsible for mild colds) could not reproduce within human cells without a working copy of two virus genes dubbed E1A and E1B. For over 10 years, this finding wasn_t appreciated, as little was known about Rb and p53. Only five years ago did researchers learn that the proteins encoded by E1A and E1B are the tools the adenovirus uses to sabotage the cell_s tumor suppressors, so that the adenovirus can replicate itself within the human cell. Inside a human cell, the virus E1A protein disables the cell_s Rb, allowing the virus DNA to use the cell_s machinery to replicate copies of itself. Meanwhile, the E1B protein inactivates p53. With the watchdog p53 no longer able to prevent the cell from replicating damaged or foreign DNA, the adenovirus is free to replicate.

In 1992 Frank McCormick, a biochemist from ONYX Pharmaceuticals in Richmond, California, realized that because adenovirus must turn off Rb and p53 to replicate, an adenovirus without E1B could not disable these tumor suppressors and would be unable to grow in healthy cells_but it would grow just fine in cells lacking Rb and p53! What human cells lack Rb and p53? Lung cancer cells! Lung cancers caused by cigarette smoking would have tumor suppressor genes mutated by benzo (a) pyrene. If McCormick was right, adenovirus with disabled E1A would not grow in normal human cells, but would grow in and destroy lung cancer cells with defective Rb. Similarly, adenovirus with disabled E1B would grow in, and destroy, lung cancer cells with defective p53.

FIRST TESTS ARE VERY ENCOURAGING
Initial studies have focused on E1B, which is easier to work with than E1A. The first results, reported over previous years, have been very promising. In tissue culture, the E1B-negative adenovirus does not grow in healthy skin cells, but does grow in a wide variety of tumor cells, including colon and lung cancer cells. When human tumor cells are introduced into mice lacking an immune system and allowed to produce substantial tumors, 60% of the tumors simply disappear when treated with E1B-deficient adenovirus, and do not reappear later. Initial human trials have been started.

A TECHNICAL HURDLE
While E1B-deficient adenovirus offers great promise as a therapy for a wide range of cancers, including most lung cancers, a significant technical hurdle remains. Recall that the initial animal tests were done on mice with no immune system. Humans have active immune systems. In cancer patients, the adenovirus therapy may be neutralized by the patient_s immune system before the virus has a chance to do any good, simply because most people have had adenovirus colds in the past and so can be expected to carry antibodies directed against adenoviruses. In these people, such antibodies might attack any E1B-deficient adenovirus introduced to fight cancer. Anticipating this problem, investigators are exploring alternative viruses that would not provoke an immune response. Molecular therapies such as those described here are only part of a wave of potential treatments under development and clinical trial. The clinical trials will take years to complete, but by the turn of the century_only two years away_we can expect to greet a new millennium in which lung cancer may become a curable disease.