UNC study supports role of circadian clock in response to chemotherapy

CHAPEL HILL, 14 jan 2009 – For years, research has hinted that the time of day that cancer patients receive chemotherapy can impact their chances of survival. But the lack of a clear scientific explanation for this finding has kept clinicians from considering timing as a factor in treatment.

Now, a new study from the University of North Carolina at Chapel Hill has suggested that treatment is most effective at certain times of day because that is when a particular enzyme system – one that can reverse the actions of chemotherapeutic drugs – is at its lowest levels in the body.

The study, performed in mice, could also have implications for the prevention of new cancers.

The enzyme system implicated – called nucleotide excision repair– repairs many types of DNA damage that come not just from chemotherapy but also from the ultraviolet rays of the sun. Thus, by understanding the cyclical nature of this system, physicians may be able to pinpoint when it is most crucial for people to protect themselves from sun exposure to minimize their risk of skin cancer.

"Timing is everything, and here we have molecular data showing why this is especially true with regard to cancer," said senior study author Aziz Sancar, M.D., Ph.D., a member of the UNC Lineberger Comprehensive Cancer Center and Sarah Graham Kenan professor of biochemistry and biophysics in the UNC School of Medicine. Sancar is also a member of the National Academy of Sciences and the Turkish Academy of Sciences. "By hitting cancer cells with chemo at a time when their ability to repair themselves is minimal, you should be able to maximize effectiveness and minimize side effects of treatment."

The study, set to appear this week in the online early edition of the Proceedings of the National Academy of Sciences, provides the first solid evidence that the daily oscillations of the cell's repair machinery can affect the potency of cancer drugs.

The primary driver of this oscillatory behavior is the circadian clock, which keeps the biochemical, behavioral and physiological processes of many organisms, including mice and humans, on a 24-hour cycle. Every single cell in the body – whether from the kidney, liver or heart – has its own internal clock, and each of these are synchronized and coordinated by one master clock, located in a particular cluster of neurons in the brain.

Because of the important role that the circadian clock plays in regulating the daily rhythms of life, Sancar wanted to see what influence it had on important functions in the body, in particular the repair of damage to DNA caused by chemotherapy or UV radiation. This damage is usually repaired by a process called nucleotide excision repair, which cuts out and replaces sections of damaged DNA.

Sancar and his colleagues studied the behavior of the repair machinery in cerebrum or brain tissue of mice over the course of a day, and found that the ability to repair damage was at a minimum in the early morning and reached a maximum in the evening hours. They then looked at each of the six components that make up the repair machinery and found that the levels of one of them – the enzyme XPA – rose and fell in synchrony with the oscillations of the circadian clock. Thus, the researchers demonstrated that the cell's ability to repair damage is linked to the circadian clock, and that this daily oscillation is ultimately due to changes in the levels of one particular enzyme at different times of day.

Sancar now wants to extend these studies to determine whether the same cyclical changes in repair activity seen in mouse brain can also be observed in mouse testis. This avenue is particularly relevant because cisplatin – a chemotherapeutic agent commonly used to treat testicular cancer – kills cancer cells by damaging DNA.

While cisplatin is considered by many people to be a miracle drug – it completely cured Lance Armstrong – one in ten patients who take it still do not survive and it is not as effective on other cancers, such as colon, ovarian and lung cancers. Sancar said he believes that identifying the times when the cancer cells' ability to repair damage is at a minimum may enable clinicians to tailor treatment and improve the survival rate for people with testicular cancer and these other more common cancers as well.

He also would like to see his findings being used for cancer prevention. Because the enzyme Sancar identified also repairs damage caused by sunlight, he plans to determine if the repair capacity in human skin changes as a function of the time of day.

"If we show the same patterns in humans as we did in mice, then it could tell us when would be the safest time to be in the sun (2 p.m. to 6 p.m.), and when would be the best time to avoid sun exposure (6 a.m. to 10 a.m.)," Sancar said. "The new information could help us prevent skin cancers."

###

The research was supported by the National Institutes of Health. Study co-authors from UNC department of biochemistry and biophysics include the lead author and postdoctoral scientist Tae-Hong Kang, Ph.D.; senior research associate Joyce T. Reardon; and postdoctoral scientist, Michael Kemp, Ph.D.

How eating fruit and vegetables can improve cancer patients' response to chemotherapy

UC Riverside study describes how naturally occurring apigenin facilitates the death of cancer cells

RIVERSIDE, Calif., 23 oct 2008 – The leading cause of death in all cancer patients continues to be the resistance of tumor cells to chemotherapy, a form of treatment in which chemicals are used to kill cells.
Now a study by UC Riverside biochemists that focuses on cancer cells reports that ingesting apigenin – a naturally occurring dietary agent found in vegetables and fruit – improves cancer cells' response to chemotherapy.
Xuan Liu, a professor of biochemistry, and Xin Cai, a postdoctoral researcher working in her lab, found that apigenin localizes tumor suppressor p53, a protein, in the cell nucleus – a necessary step for killing the cell that results in some tumor cells responding to chemotherapy.
The study, published this week in the online early edition of the Proceedings of the National Academy of Sciences, provides a novel approach to conquer tumor resistance to chemotherapy, and suggests an avenue for developing safe chemotherapy via naturally occurring agents.
Normally, cells have low levels of p53 diffused in their cytoplasm and nucleus. When DNA in the nucleus is damaged, p53 moves to the nucleus where it activates genes that stop cell growth and cause cell death. In this way, p53 ensures that cells with damaged DNA are killed.
In many cancers, p53 is rendered inactive by a process called cytoplasmic sequestration. Apigenin is able to activate p53 and transport it into the nucleus, resulting in a stop to cell growth and cell death.
"In therapy you want to kill cancer cells," explained Cai, the first author of the research paper. "But to stop cell growth and to kill the cell, p53 first needs to be moved to the cell's nucleus to function. Apigenin is very effective in localizing p53 this way."
Apigenin is mainly found in fruit (including apples, cherries, grapes), vegetables (including parsley, artichoke, basil, celery), nuts and plant-derived beverages (including tea and wine). It has been shown by researchers to have growth inhibitory properties in several cancer lines, including breast, colon, skin, thyroid and leukemia cells. It has also been shown to inhibit pancreatic cancer cell proliferation.
"Our study advocates the inclusion of vegetables and fruit in our daily diet to help prevent cancer," said Liu, the research paper's coauthor.
###
The National Institutes of Health supported the five-year study.

Most Cancer Survivors Say Chemo Fears Unfounded


FRIDAY, April 4 -- Although most cancer survivors polled in a recent survey said they had been fearful of undergoing chemotherapy, most also said the treatments were much less trying than they had expected.
In fact, 94 percent said they would advise others to undergo chemotherapy if their doctor recommended it.
"Like most people, I was filled with fears about chemotherapy, particularly about the possible side effects," said award-winning broadcast journalist and author Linda Ellerbee, 63, who underwent a double mastectomy and chemotherapy after being diagnosed with breast cancer 16 years ago.
Ellerbee spoke at a recent news briefing in New York City, convened to announce the results of the survey.
"It wasn't fun -- no one will tell you that chemotherapy is fun. But it wasn't as bad as I expected, either," Ellerbee said. "The reality is that I believe that I am here today, partly because that treatment worked."
Ellerbee, for decades a renowned journalist at CBS, NBC and then PBS, is also the author of a number of books for both children and adults. The mother of two, she now writes and hosts Nick News for Nickelodeon.
The survey -- which polled 326 U.S. adults who had undergone cancer chemotherapy within the past five years -- was sponsored by the nonprofit National Coalition for Cancer Survivorship (NCCS) and drug maker Sanofi-Aventis, who together have created the Surviving With Confidence campaign to help patients gain a better understanding of cancer care.
Some of the survey's findings:Around eight out of 10 cancer survivors said they had been fearful prior to starting chemotherapy, with most (76 percent) worried primarily about side effects such as hair loss, nausea and fatigue. Looking back, almost two-thirds (62 percent) said those fears were unjustified. Just 14 percent described their side effects as "very difficult," and about a third (32 percent) had a "somewhat easy" or "very easy" experience with treatment. Almost all (87 percent) of survivors said that new supportive care products made the side effects that they did experience much more manageable than they had expected. Eighty-seven percent of survivors who had experienced side effects said that chemotherapy was worth going through, and 90 percent said the treatments had given them real hope for survival.
Anne Willis, 25, is NCCS' director of survivorship programs and a 10-year survivor of Ewing's sarcoma, a rare malignancy that attacks the bone or soft tissue. She told conference attendees that when she first knew she would be undergoing chemotherapy, she "was too scared to ask the nurses what to expect. I never had any conversations with anybody, so I was absolutely terrified."
But, like many of those polled in the survey, Willis said she soon realized that her fears of chemotherapy were exaggerated. Her attitudes toward her health-care team changed, too. "I became much more of an active participant in my care," Willis said. "I never hesitated if I had a problem. One time I had a full-body rash that did not make me very popular, and I immediately told my doctor about it. We treated it and took care of the problem."
Too often, patients remain mum about their fears and the side effects that they do experience. Ellerbee said she was lucky, because her training as a journalist had taught her to ask questions.
"If you are living with cancer, talk to your doctors and other health professionals about these issues," she advised. "If you've got fears, tell them. If you have questions, ask them. Side effects -- tell them. Ask what they can do to help you."
The NCCS strongly advises that patients also get written "Treatment Plans" from their health-care team before they begin chemotherapy -- a document that outlines the interventions they will receive; potential side effects; and ways to manage those side effects.
"I know personally that having that piece of paper would have encouraged me to open up that dialogue with my health-care team," Willis said.
Everyone agreed that, if anything, cancer care has gotten both easier and more effective in the decade or more since Willis and Ellerbee received their care.
"Things are dramatically different now in the 10 or 12 years since [Willis'] treatment, in terms of what we can do for patients to improve their care," said oncologist Dr. Howard Burris, who is chief medical officer and director of drug development at the Sarah Cannon Research Institute in Nashville, Tenn. "It's really made cancer care an outpatient business."
Ellerbee agreed. "Since my diagnosis, there have been many advances in cancer care, and more people survive every year because of new treatment options," she said. "In other words, it is more possible today to live life as you know it -- and to have that life as you know it go on -- while you are undergoing therapies that can potentially extend your life or save your life."
"It has been 16 years since I was diagnosed with cancer," Ellerbee added, "and every morning that I wake up on the right side of the grass, I am a grateful woman, because I did not let my fears keep me from getting the treatment that I needed."

Chemotherapy boosts heart disease risk

By LAURAN NEERGAARD, AP Medical WriterMon Oct 8, 3:52 PM ET
Breast cancer survivors may face increased risk of heart disease — and doctors are debating if it's time to largely abandon a chemotherapy mainstay that is one reason for the problem.
Drugs called anthracyclines are a breast chemo staple despite a well-known risk: They weaken some women's hearts. What's new is research suggesting the drugs work no better than safer alternatives for most women.
It's a controversy born of success: Treatment advances are enabling more women than ever before to beat breast cancer, and some 2.4 million survivors are alive today. Now a move is under way to determine just how many women are vulnerable to heart disease because of their cancer battle, and how to help them.
Chemo is only one cardiac culprit. Other factors play a role, too: Chest radiation, the weight gain that plagues many survivors, physical inactivity during treatment and stress.
"In the process of curing their breast cancer, we've exposed them to some pretty nasty things. And it's not just one nasty thing, it's a sequence of nasty things," explains Dr. Pamela Douglas, a Duke University cardiologist who is planning research into how to protect these women's hearts.
"This is really coming at you from all sides," says Douglas, who outlined the "multiple hits" in this month's Journal of the American College of Cardiology.
But much of the debate centers on who should use anthracyclines, including the best-known Adriamycin, that can damage heart muscle, sapping its pumping strength.
Dr. Dennis Slamon of UCLA's Jonsson Cancer Center cites nine studies, here and abroad, that conclude that only the 20 percent of patients whose tumors have an overactive gene called Her2 are specifically sensitive to anthracyclines.
Then Slamon's closer inspection found that not all Her2 patients are alike — and only those who have a second overactive gene, called TopoII, derive special benefit from anthracyclines. That's about 8 percent of breast cancer patients.
The powerful Her2-targeting drug Herceptin — key for women with Her2-positive tumors — also comes with a heart-damage warning. But adding it to anthracyclines increases the heart risk fivefold, with no extra benefit, Slamon found.
Outright heart failure during chemo is rare, around 2 percent of patients. But Douglas cites research that anywhere from 10 percent to half of anthracycline users experience more subtle heart weakening, making them more vulnerable to aging's usual rigors, like high blood pressure and cholesterol.
And in this month's Journal of Clinical Oncology, researchers tracked breast cancer survivors ages 66 to 70 who had undergone chemo 10 years earlier. Those who had received an anthracycline were 26 percent more likely to have developed heart failure in the following decade than those on different chemo.
"It's almost like the perfect storm," Slamon says of all the research. "We're adding no incremental benefit with plenty of incremental toxicity."
Now the influential National Breast Cancer Coalition is lobbying oncologists and government regulators to reconsider treatment guidelines.
"These are very strong, very real data that they need to pay attention to," says coalition president Fran Visco.
But many oncologists aren't convinced, and want more evidence that other chemos work as well.
Indeed, Duke University is beginning a major study funded by the Defense Department to do additional genetic testing on Her2-negative women, to compare Adriamycin to the non-anthracycline Taxotere.
"It's fair to say I'm using less Adriamycin for truly early stage" cancer, says lead researcher Dr. Kelly Marcom, Duke's breast oncology chief.
"But there are still patients that I think have cancers that may be more sensitive to Adriamycin," Marcom adds. The jury is still out."
However that controversy ends, a bigger question is how to find and help survivors with heart damage from any cause. As Jane Sartin of Providence, N.C., learned, symptoms are sneaky.
Sartin underwent a mastectomy for side-by-side breast tumors, and took Adriamycin followed by Herceptin. She was warned about heart side effects, and knew as an overweight smoker she already was at risk. Yet she blamed the surgery when she got winded.
"I had never said anything to my doctor about it. I'd say, 'I'm tired, I think from the surgery,'" recalls Sartin, 45.
Twice her ejection fraction — a measure of blood pumped per beat — dropped well below normal. It bounced back with treatment changes, and Sartin believes her cancer therapy's benefit justified the side effect.
"I really felt like, hey, I can deal with anything as long as I'm alive," says Sartin, who now is dieting and weaning herself from cigarettes.
For now, never shrug off heart-related symptoms, stresses Dr. Ann Bolger of the University of California, San Francisco, an American Heart Association spokeswoman. Early care can be lifesaving.
Duke's Douglas recommends that all breast cancer patients get a formal heart risk assessment before oncologists decide final treatment. It might sway cancer therapy, or signal who'll need extra heart care later.