It’s a legacy of war that nobody wanted: the lingering effects of the tactical herbicide called Agent Orange. This was “scorched earth” warfare – destroying vegetation to clear the countryside of places for the enemy to hide – taken to the next level, with 20 million gallons of chemical defoliants sprayed by the U.S. military in Southeast Asia between 1962 and 1971.
Nobody knew just how bad an idea this was until after the war, when the more than 2.5 million U.S. soldiers (and an estimated 4 million soldiers and civilians in Vietnam) who were exposed to Agent Orange – those who sprayed it on the battlefield, and those who loaded barrels of it onto trucks and trains at supply depots here in the U.S. – started reporting major health problems, including cancer.
Many have developed prostate cancer, and every year, more Vietnam veterans are diagnosed with the disease. Worse, “the men who were exposed to Agent Orange and other battlefield chemicals often present with more aggressive prostate cancer,” says Jeffrey Jones, M.D., Chief of Urology at the Michael E. DeBakey Veteran Affairs Medical Center (MEDVAMC).
Why is this? Nobody knows the exact nature of the genetic reprogramming that makes those exposed to Agent Orange more susceptible to cancer. As part of a partnership between the VA and the Prostate Cancer Foundation (PCF), Jones and colleagues have been awarded a grant to find some long-overdue answers, using a massive database of medical samples from thousands of veterans. “The MEDVAMC is one of the largest primary and tertiary care centers for veterans,” Jones notes. “We treat hundreds of men with localized and metastatic prostate cancer every year.” Of these, between 5 and 10 percent have been exposed to battlefield chemicals such as Agent Orange. Unlike many studies, in which African-American men are underrepresented – despite the fact that these men, along with men who have a family history of prostate cancer, are at higher risk of getting it – black and Caucasian men “are equally represented in our patient cohort.”
What was in this stuff? There were several of these “rainbow herbicides” used during the war as part of Operation Ranch Hand – including blue, green, pink, white, and purple agents – but orange was the biggie. Its worst ingredient was TCDD (tetrachlorodibenzo-P-dioxin), a particularly vile member of a nasty family of chemical compounds called dioxins. There’s no getting around it: dioxins are highly toxic, even in small amounts.
Although the why – the link between prostate cancer and Agent Orange – is clear, the how – what happens on a molecular level to make men not only more susceptible to getting the disease, but to developing a higher grade of cancer that is more difficult to treat – is not understood, says Jones. He is particularly interested in environmentally caused epigenetic changes: micro-alterations to the DNA that could make a gene unable to function properly or, when such changes happen as cancer is progressing, act as an accelerant on a fire, making the flames grow and spread faster. One of these changes is methylation, the accumulation of extra baggage on DNA, like barnacles on a whale. These are tiny changes, but – think of rust on a key, so it no longer fits into a lock – they can add up. These changes may be fast-forwarded in men who already have a higher risk of developing prostate cancer. Learning what to look for could help scientists predict a man’s risk of developing aggressive cancer and his risk of recurrence of cancer after treatment. It also may identify new targets for treating high-risk or advanced cancer.
In biopsy tissue, pathology specimens, banked blood, urine, and other samples, Jones and colleagues are searching for environmentally caused epigenetic changes in the genes. Looking for such evidence is not easy, he notes. “It’s not something that you just order a test and you get the answers; it takes quite a bit of ingenuity to get the results that we’re looking for.”
Using highly sophisticated technology, the investigators will also be looking at metabolomics, the distinctive metabolic fingerprint within prostate and prostate cancer cells, and transcriptomics, the genes being expressed in these cells. They will study epigenetic factors using DNA microarrays, chips that can analyze thousands of genes at a time. Because scientists have found important distinctions in how prostate cancer presents and develops based on race – cancer tends to start in a different area of the prostate in African-American men, for example, and tends to be more aggressive – Jones and colleagues will be looking at racial differences, including possible mutations in androgen (male hormone) receptors.
Studies involving environmental factors always begin with epidemiology, Jones notes. “We don’t have mechanistic answers for a lot of health-related problems right away. We start to see pockets of differences in the occurrences of a specific event, and then we start looking for the cause.” For example, if a bunch of people turn up at the hospital with food poisoning, the first thing investigators need to do is backtrack: “What did you eat? Where did you eat it? Then you isolate where the food poisoning is coming from. There is a clear clustering of cancer in men who were exposed to Agent Orange. We don’t know how it’s happening. We know who was in the exposure zones. We can estimate to some degree the relative exposure. We’re trying to understand the dose of exposure to change in gene expression,” and then move on to understanding the “carefully orchestrated cellular processes” that are driving the cancer.
Jones wants veterans to know this: “We are concerned about your health. If you were exposed to Agent Orange, we want to understand the factors that predispose you to developing prostate cancer, and we want to prevent future veterans from getting sick. We also want to treat those who have the disease, and we hope this research will give us better targets for therapy, and better means to diagnose and treat prostate cancer.”
Even though the men exposed to Agent Orange may share the same cause of prostate cancer, Jones notes, “it doesn’t look like there will be a ‘one-size-fits-all’ treatment that will work for all veterans. We will need to individualize therapy based on the patterns of their tumor. That’s why we’re trying to understand the individual behavior of these tumor cells, so we can design better therapeutics to stop the cancers from growing.”
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