Journal of the National Cancer Institute Advance Access originally published online on August 28, 2007
JNCI Journal of the National Cancer Institute 2007 99(17):1288-1289; doi:10.1093/jnci/djm146
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© Oxford University Press 2007.
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Pregnancy Problem Yields Insight Into Cancer Drug–Induced High Blood Pressure
Blood vessel growth, or angiogenesis, is a popular target in cancer therapies these days. After all, cancers need blood to grow, so cutting off their supply can choke them to death. Three approved, effective drugs all inhibit the same key molecule that simulates angiogenesis, but they all seem to have a similar side effect: high blood pressure.
No one is sure how these drugs cause high blood pressure, but research in renal cancer and a pregnancy complication called preeclampsia offers one intriguing hypothesis. Women with preeclampsia have dangerously high blood pressure, and renal cancer biologist Vikas Sukhatme, M.D., Ph.D., at Beth Israel Deaconess Medical Center in Boston suggests that the cancer drugs cause high blood pressure in the same way that it does in some pregnant women.
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"There are parallels in toxemia in pregnancy," says oncologist Joseph Paul Eder, M.D., of AstraZeneca in Waltham, Mass., who was not involved with Sukhatme's work.
Hypertension Risk Factor
The three drugs target a protein called VEGF, or vascular endothelial growth factor, which cancer cells produce to instigate blood vessel growth. The prototype VEGF inhibitor, bevacizumab (Avastin), binds directly to VEGF and hampers its ability to drive angiogenesis. The other two drugs, sorafenib (Nexavar) and sunitinib (Sutent), interfere with the proteins that VEGF stimulates on blood vessel cells. Also, "there are a whole bunch of VEGF inhibitors working their way to clinic," Eder says.
No one knows how many patients get high blood pressure from the drugs. Different studies show different percentages of hypertension cases, ranging from about 20% to 36%. Anywhere from 4% to 10% of these cases are severe enough to warrant treatment. But the drugs probably affect a higher proportion than those numbers suggest. In a small 2006 study published in the Journal of Clinical Oncology, 12 of 20 patients on sorafenib had a rise in their blood pressure of at least 20 mmHg. Normal systolic blood pressure (the top number) is less than 130 mmHg, and people generally go on hypertensive drugs if they maintain pressure more than 140 mmHg. So depending on an individual's starting point, an extra 20 mmHg can put one over the edge. Sukhatme says that a gradual raising of blood pressure, as happens in most people with hypertension, is not as dangerous as, for example, jumping from 120 mmHg to 180 mmHg over 6 hours.
The consensus appears to be that high blood pressure is a workable risk factor compared with the benefits of the anti-VEGF drugs. "The value of the agents has been clearly demonstrated so far. People are willing to deal with the hypertension issues. That doesn’t make it a bad drug," says Thomas Hutson, D.O, Pharm.D., of the Baylor Sammons Cancer in Dallas. Eder agrees. "The blood pressure side effects of VEGF inhibitors are not deal breakers," he says.
However, the experts also say that it's important to monitor and treat the blood pressure when necessary. "If the drug keeps you alive, we should use it. But we also don’t want you to stroke out from high blood pressure," Sukhatme says. Renal oncologist Brian Rini, M.D., at the Cleveland Clinic says that managing high blood pressure is like managing any risk factor in cancer patients.
Clamping Down on VEGF
Cancer cells haven’t cornered the market on VEGF. The protein is critical during development, when new blood vessels are forming. It is also important during pregnancy. The placenta helps supply blood to the growing fetus and produces some proteins of its own. Most notably, the placenta pumps out a receptor protein to VEGF called Flt-1, which normally allows VEGF to stimulate cells on which Flt-1 resides. However, a version called sFlt-1 does not remain on cells but can be found free-floating in the blood.
The placenta has long been a suspect in the cause of preeclampsia. In preeclampsia, blood pressure in pregnant women shoots up. The high blood pressure can hurt or kill both the woman and the fetus. "Their blood pressure can get up to 200 mmHg or more. These women are in trouble," Sukhatme says. The kidneys are especially sensitive to high blood pressure, and damage to them sends excess amounts of kidney-derived proteins into the blood, and women often have swollen tissues. Sukhatme says that once the baby is delivered and the placenta removed, the blood pressure generally goes back down, although patients may suffer permanent damage.
One of the teams that originally showed sFlt-1 exuding from the placenta, Sukhatme and his Beth Israel colleague, nephrologist S. Ananth Karumanchi, M.D., also found that women with severe preeclampsia had a third of the amount of VEGF in their blood as healthy women. In the same study, the team found that injecting sFlt-1 into nonpregnant rats caused them to develop high blood pressure and the kidney lesions typically found in preeclampsia patients, as well as high levels of protein into their blood.
Because sFlt-1 also binds to a protein called placental growth factor, the team injected a molecule related to sFlt-1 that binds only to VEGF and got the same result, suggesting that VEGF is sufficient to cause high blood pressure in cases not involving pregnancy, such as with cancer patients. Finally, the team found that the amount of sFlt-1 in the blood of pregnant women could predict the onset of the condition several weeks before any clinical symptoms arose.
"So the fetus doesn’t have an adequate blood supply and it binds up all the VEGF in the mother," Eder says. "Without VEGF, the blood vessel cells tighten up and up goes the blood pressure."
Sukhatme agrees. "Any methodology that leads to VEGF depletion could result in a preeclampsia-like condition." He argues that cancer patients on the anti-VEGF drugs are in this same state, but "nobody has been biopsying anti-VEGF patients to see if they have the preeclampsia [kidney] lesion."
Getting Along
At this point, Sukhatme thinks that a test for sFlt-1 might identify pregnant women who will come down with preeclampsia, but oncologists don’t have such an obvious smoking gun. Physicians can’t say which cancer patients will suffer high blood pressure. "We end up having to watch patients closely," Hutson says. "Except for those patients with preexisting hypertension, we don’t know who's most susceptible." Trying to understand two things would be helpful in managing cancer patients: determining who is most at risk and whether one class of antihypertensive medication works best for cancer patients and has the fewest drug–drug interactions.
Eder says that understanding how a lack of VEGF causes high blood pressure could help doctors choose the better antihypertensive medication. "It's chaotic. We have 40-odd drugs to deal with hypertension," he says. For example, some evidence suggests that VEGF normally increases production of nitric oxide, which keeps vessels relaxed. In the absence of VEGF, a drug that blocks so-called calcium channels on blood vessel cells raises the amount of nitric oxide. "So you’d think that some calcium channel blocker would have an effect," Eder says.
However, other researchers think that VEGF keeps blood pressure down by increasing the number of tiny blood vessels. Work in retinal damage due to diabetes suggests that there is not enough VEGF around to grow these microvessels, which in turn leads to higher blood pressure.
While cell biologists work out the details of VEGF and hypertension, oncologists will continue to keep an eye on their patients, especially in the first few weeks of cancer therapy, Hutson says. The good news is that serious complications don’t arise too often: "I don’t think I’ve ever had to stop somebody's anticancer drug totally," Rini says. After taking patients off anti-VEGF drugs, "the hypertension resolves over time," Sukhatme says. And that's sounds like giving birth to the best of both worlds.
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