Nav: Home

New Approach To Multidrug Resistance

August 13, 1997

Dartmouth researchers have found a way to dramatically restore the effectiveness of chemotherapy in cancer cells that have become resistant to its effects. The technique temporarily inhibits production of a prime protective mechanism used by tumors -- a molecular pump called P-glycoprotein that flushes drugs out of cells. The study, conducted by Associate Professor of Pharmacology and Toxicology Joshua Hamilton at Dartmouth Medical School, with colleagues from the medical school and the Norris Cotton Cancer Center, is reported in the current issue of Clinical Cancer Research.

One of the greatest obstacles to successful cancer treatment is the development of multidrug resistance by tumors -- that is, tumors become better able to withstand the actions of a wide variety of unrelated chemicals. The anti-drug pump is a major tool in multidrug resistance.

The researchers have found a novel way to suppress production of the pump long enough for cancer drugs to work.

Therapies for cancer treatment often use chemicals that impair the genetic machinery of cells. In previous studies, the Dartmouth researchers found that relatively low doses of these DNA-damaging drugs affect genes selectively. Genes active in day-to-day housekeeping -- for example, those involved in cell structure or basic food metabolism -- are less vulnerable to damage than genes induced in response to external signals -- such as hormone fluctuations or an incursion of foreign chemicals. Because the gene for P-glycoprotein is inducible, activated by cues from its environment, investigators were interested in how it would be affected by cancer chemotherapy drugs. They focused initially on one group of drugs called DNA cross-linking agents, which damage genes by fusing strands of their DNA together.

The researchers treated drug-resistant cells with a low dose of the cancer drug mitomycin C, waited 24 hours, then administered a second chemotherapy agent. The low-dose pre-treatment appeared to temporarily turn off the gene that produces P-glycoprotein, producing a "window" of time during which there was an increase in the sensitivity of the cells to the killing effect of the second drug. The researchers achieved similar results by priming cells with three other cross-linking drugs.

"Opening the window takes about 24 hours, and it stays open for another 72 hours -- and that's the period when the second drug is most effective," says Hamilton. The researchers report similar results in drug-resistant cells derived from breast, colon, liver, leukemia and brain tumors. Preliminary results from animal and human studies, using paclitaxel (Taxol), doxorubicin and mitomycin, are consistent with these findings.

The results suggest that a similar pretreatment regimen may increase the efficacy of cancer chemotherapy in patients. Sequential use of chemotherapeutic agents would minimize drug interactions as well as side effects.

The researchers are now doing animal studies to determine the most effective combination of drugs, and human clinical trials to determine the effectiveness of this approach in various natural cancers.

The Dartmouth team includes Michael Ihnat, Jean Lariviere, Amy Warren, Nicole La Ronde, Johanna Blaxall, Karana Pierre and Bruce Turpie. The work was supported by grants from the National Cancer Institute, the International Life Sciences Institute Inc., the American Cancer Society and the Cotton Cancer Center.
-end-

Contacts: Nancy Serrell
Science Writer
Dartmouth College
603/646-3661
nancy.serrell@dartmouth.edu
or
Joshua Hamilton
Associate Professor of Pharmacology & Toxicology
Dartmouth Medical School
603/650-1316
Joshua.W.Hamilton@Dartmouth.EDU

The Geisel School of Medicine at Dartmouth

Related Chemotherapy Articles:

Chemotherapy drug may increase vulnerability to depression
A chemotherapy drug used to treat brain cancer may increase vulnerability to depression by stopping new brain cells from growing, according to a new King's College London study out today in Translational Psychiatry.
Sperm changes documented years after chemotherapy
A Washington State University researcher has documented epigenetic changes in the sperm of men who underwent chemotherapy in their teens.
Depressed patients are less responsive to chemotherapy
A brain-boosting protein plays an important role in how well people respond to chemotherapy, researchers report at the ESMO Asia 2016 Congress in Singapore.
Breast cancer study predicts better response to chemotherapy
It is known from previous research that the ER-beta estrogen receptor often has a protective effect.
Personalizing chemotherapy to treat pediatric leukemia
A team of UCLA bioengineers has demonstrated that its technology may go a long way toward overcoming the challenges of treatment for acute lymphoblastic leukemia, among the most common types of cancer in children, and has the potential to help doctors personalize drug doses.
How gut microbes help chemotherapy drugs
Two bacterial species that inhabit the human gut activate immune cells to boost the effectiveness of a commonly prescribed anticancer drug, researchers report Oct.
Molecule prevents effect of chemotherapy
For the last three years the research team has been working on the development of a so-called biomarker to predict treatment effectiveness.
Study provides new clues to leukemia resurgence after chemotherapy
For the first time, researchers have discovered that some leukemia cells harvest energy resources from normal cells during chemotherapy, helping the cancer cells not only to survive, but actually thrive, after treatment.
Dialing up chemotherapy for pancreatic cancer with ultrasound
Researchers at Haukeland University Hospital in Bergen, Norway have combined a laboratory ultrasound technique called 'sonoporation' with the commercially-available chemotherapy compound Gemcitabine to increase the porosity of pancreatic cells with microbubbles and to help get the drug into cancer cells where it is needed.
Vitamin A may help improve pancreatic cancer chemotherapy
The addition of high doses of a form of vitamin A could help make chemotherapy more successful in treating pancreatic cancer, according to an early study by Queen Mary University of London.

Related Chemotherapy Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#SB2 2019 Science Birthday Minisode: Mary Golda Ross
Our second annual Science Birthday is here, and this year we celebrate the wonderful Mary Golda Ross, born 9 August 1908. She died in 2008 at age 99, but left a lasting mark on the science of rocketry and space exploration as an early woman in engineering, and one of the first Native Americans in engineering. Join Rachelle and Bethany for this very special birthday minisode celebrating Mary and her achievements. Thanks to our Patreons who make this show possible! Read more about Mary G. Ross: Interview with Mary Ross on Lash Publications International, by Laurel Sheppard Meet Mary Golda...