By David N. Leff

The next time you chow down on a broiled hamburger or crispy fried chicken drumstick, bear in mind you¿re ingesting a carcinogen known as a bulky-adduct-forming agent. Cigarette tar and smoke also may fall in this cancer-causing category.

Methylating agents are in another carcinogenic class, ¿which can be built in our intestines,¿ observed research oncologist Christoph Lengauer. ¿That perhaps is a reason why we find mismatch repair gene defects in colorectal cancer.¿

Lengauer is senior author of a paper in today¿s Proceedings of the National Academy of Sciences, dated May 8, 2001, titled: ¿Carcinogen-specific induction of genetic instability.¿

¿For the first time,¿ he told BioWorld Today, ¿we find a connection between a major genetic pathway in cancer ¿ genetic instability ¿ which is a driving force for generating malignancy and the carcinogenic environment the tumor is always exposed to.

¿A tumor needs several mutations,¿ Lengauer explained, ¿in order to develop. It takes more than just one gene. When people measured the background rate, or the failure rate, of normal cells, they found out that the probability of getting cancer would be far too low. That is, a background rate of creating genetic mistakes is too low to allow for the number of mutations we know are required for a tumor to develop. People had proposed some sort of driving force,¿ he continued, ¿which is genetic instability, which accelerates the rate of mutation.¿

Gene Mutations Pile Up In Tumors

¿It¿s a rather new field,¿ he pointed out. ¿Nevertheless, seven years ago, oncologist Bert Vogelstein and his collaborators at the Johns Hopkins University Oncology Center in Baltimore reported the first experimental evidence that such a form of instability exists in human cancers. They found mutations in a hereditary form of colorectal cancer in mismatch repair genes. These are the genes that look for mistakes after DNA replication, and fix them.¿ Lengauer is an assistant professor of oncology at the Hopkins center.

¿When you have a mutation,¿ he explained, ¿one of those mismatch repair genes, rather than fixing those mistakes, accumulates them, because your repair mechanism is defective. By chance, you get mutations in genes that are intrinsically important for cancer to develop. These mismatch repair genes are responsible for about 15 percent of colorectal cancers.

¿We found two or three years ago in our lab that the other 85 percent of colorectal cancers have a different form of instability ¿ chromosomal. Those tumor cells have a defective checkpoint, which is a surveillance mechanism that controls chromosomal segregation, when a cell divides.

¿What happens is unequal distribution of chromosomes toward the two new daughter cells,¿ Lengauer described. ¿That¿s chromosome instability. It could also lead, when you lose a chromosome, to an accumulation of mutations in cancer, and it¿s the commonest feature of solid tumors ¿ abnormal chromosome number ¿ i.e., aneuploidy.

¿That¿s analogous to mismatch repair genes,¿ he pointed out. ¿One is at a DNA sequence level, the other at a chromosomal level. And we knew that a mutated mismatch repair gene can be inherited ¿ and the second copy of that gene gets mutated during your lifetime from environmental carcinogens.

¿It¿s more complicated for chromosomal instability,¿ Lengauer went on, ¿because we just found one human gene so far where we know it can cause that defect. We found mutations there, which can be caused by exposure to carcinogens. BUB1,¿ he explained, ¿is a mitotic spindle checkpoint gene. Checkpoint means it¿s controlling or surveilling the segregation of chromosomes, in order to make sure that both halves get the same amount of chromosomes.¿

Survivors Set Tone For Rethinking Therapy

Lengauer recounted the cell culture experiments that confirmed his team¿s hypothesis:

¿We took human cells that did not have any form of instability and exposed them with different kinds of carcinogens, known from epidemiology to play a major role in development of cancers. We picked representatives of the two major groups: one, methylating agents; the other, we refer to as bulky-adduct-forming agents, because that¿s the way these complexes place themselves along the DNA strands.

¿When we exposed the cells with either one of those carcinogens,¿ he recounted, ¿most of them died. They could not deal with that traumatic experience ¿ so much toxic carcinogen around. Just a few cells survived that exposure. We analyzed those survivors ¿ their genes, their genetic pathway ¿ and found that when they¿re exposed to one of the methylating agents, all the cells we could grow out and survive that process have a defect in mismatch repair.

¿Perhaps we should change our thinking about cancer therapy,¿ Lengauer mused, ¿for the following reason: Many of the drugs that we use in cancer chemotherapy are toxic to cells. When dealing with a tumor that has a mismatch repair defect, you would never want to treat that tumor with a methylating agent, because they don¿t care for that. That¿s why they were selected to be cancerous in the first place.

¿On the other hand, you would never want to use something like a bulk-adduct-forming agent to treat chromosome instability, because it wouldn¿t help. We have that problem right now. We use chemotherapeutic drugs and in some cases they work, in others they don¿t ¿ and we don¿t understand why. So all our clinical trials and studies should include genetic profiling of the patient, and of the individual tumor. Because we could link that to the way the tumor responds to our chemotherapeutic drugs.

¿In an ideal world,¿ he suggested, ¿we will have cancer drugs designed specifically for an individual patient. What we are doing right now, we know, makes no sense. There¿s no cancer drug out there that can work on everybody.

¿So far, the only discretionary environmental carcinogens we can choose to avoid are charred meat and chicken, plus cigarettes. That¿s how life is. We have several possibilities ¿ nutrition, exposure to certain chemicals, our own lifestyle choices ¿ like fast-food chains or smoking, things like that. And then there¿s a hereditary basis, too. So when a patient comes into the oncology center for possible therapy,¿ he concluded, ¿there has to be a medical analysis and a lifestyle analysis.¿

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