Pharmacokinetics May Explain Differences in Cisplatin and Oxaliplatin Ototoxicity
More cisplatin enters the inner ear in an animal model than oxaliplatin. The difference may explain why cisplatin treatment in humans can lead to hearing problems while oxaliplatin rarely does.
The amount of cisplatin a patient can tolerate is often limited by hearing damage induced by the drug, referred to as ototoxicity. Oxaliplatin is not frequently associated with the problem, despite the fact that both drugs are platinum compounds.
To find out why the difference exists, Victoria Hellberg, M.D., at the Karolinska Institutet in Stockholm, and colleagues measured the amount of cisplatin and oxaliplatin that reached the cochlea in guinea pigs following intravenous dosing of each drug.
The total platinum concentration in the cochlea was more than five-fold higher with cisplatin than with oxaliplatin following intravenous injection. The perilymphatic drug concentration was also higher in the cisplatin-treated animals than in those exposed to oxaliplatin.
"The differences in cochlear kinetics and cellular uptake that we found in the hearing end organ are sufficient to explain the difference in ototoxicity between cisplatin and oxaliplatin," the authors conclude.
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High Insulin Level Is an Independent Risk Factor for Breast Cancer
Women who have a high level of insulin have a higher risk of developing breast cancer than women who have a lower level of the hormone.
Obesity is a known risk factor for postmenopausal breast cancer. This relationship has been attributed to the high estrogen levels in many obese postmenopausal women. Obesity is also associated with high insulin levels. However, it is not known whether high levels of insulin, which stimulates the growth of breast cells in tissue culture, are also associated with breast cancer. The current investigation was the first study to prospectively examine the role of insulin in breast cancer while controlling for estrogen levels.
In the current study, Marc Gunter, Ph.D., and Howard Strickler, M.D., of the Albert Einstein College of Medicine in New York, and colleagues, examined the association between incident breast cancer and baseline fasting insulin, insulin-like growth factor-1 (a related hormone), and estradiol levels in 835 women enrolled in the Women's Health Initiative Observational Study who developed breast cancer and a randomly-selected sample of 816 women in the study who did not develop breast cancer.
When the researchers divided the women into four groups based on their fasting insulin levels, they found that women with the highest insulin levels had nearly a 1.5-fold higher risk of developing breast cancer than the women with the lowest insulin levels. Further, the investigators separately analyzed women who were not using hormone therapy and found that, in these women, those individuals with the highest insulin levels had a 2.4-fold increased risk of developing breast cancer compared to those with the lowest levels, even after accounting for multiple other breast cancer risk factors, including estrogen levels.
"These data suggest that hyperinsulinemia is an independent risk factor for breast cancer and may have a substantial role in explaining the obesity-breast cancer relationship," the authors conclude.
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Prognostic Test for Breast Cancer May Not Detect All Tumor Types
An antibody-based test that is used to detect circulating breast cancer cells and provide prognostic information for patients during treatment may not detect all subtypes of breast cancer.
Researchers have identified five subtypes of breast cancer by their gene expression patterns. The subtypes – basal, HER2-positive, luminal A and B, and normal-like – vary in their natural history and response to therapy. CellSearch is an antibody-based test, approved by the U.S. Food and Drug Administration, to detect circulating breast cancer cells in patients before and during treatment. Previous studies suggest that women who have a decrease in circulating tumor cells after the start of treatment are likely to have a better outcome than those who do not have a decline. It was not known if the CellSearch assay detected all five subtypes of cancer equally.
In the current study, Anieta Sieuwerts, Ph.D., of the Erasmus Medical Center in Rotterdam, The Netherlands, and colleagues tested whether the assay could isolate cells of breast cancer cell lines whose subtype is known that had been added to human blood from a healthy volunteer. The investigators tested cells from a total of 34 cell lines that represented a mix of the five breast cancer subtypes.
The assay did not detect the nine normal-like breast cancer cells but did detect the other subtypes. "New tests that include antibodies that specifically recognize normal-like breast tumor cells…are needed," the authors conclude.
Anieta Sieuwerts, Ph.D., firstname.lastname@example.org, ++ 31(0)10 7044372
Also in the December 30 JNCI:
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