© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 20, 1625,
October 18, 2000
© 2000 Oxford University Press
IN THIS ISSUE |
The tyrosine kinase Bcr-Abl, which causes chronic myeloid leukemia, can be inhibited by the drug STI571. Mice injected with human leukemic cells can be cured with STI571, but treatment ultimately fails in animals that have large tumors. Gambacorti-Passerini et al. (p. 1641) explored the mechanism of this drug resistance in mice that relapsed after STI571 treatment. Tumor cells isolated from these animals were still sensitive to STI571, suggesting that a plasma protein may be inactivating STI571. They found that 
1 acid glycoprotein (AGP) bound STI571 and blocked its ability to inhibit Bcr-Abl kinase activity. Erythromycin interfered with this binding, and when erythromycin was administered with STI571, there were greater tumor reductions and better long-term tumor-free survival compared with STI571 treatment alone. The authors conclude that molecules such as erythromycin that compete with STI571 for AGP binding may enhance the therapeutic potential of STI571.
In an accompanying editorial, Sausville (p. 1626) discusses these findings in the context of other settings in which AGP has affected drug clinical effects. He points out that these results raise many questions that remain to be clarified, but he adds that the design of future trials of STI571 should take these data into consideration.
Assessing the Risk of False-Positive Mammograms
As the number of mammograms a woman has increases, so does her chance of having a false-positive mammogram. Until now, little has been known about how the characteristics of the woman herself and the characteristics of the radiologic screening she undergoes affect the cumulative risk of a false-positive mammogram. Using the medical records of 2227 randomly selected women, Christiansen et al. (p. 1657) found that the risk of a false-positive screening mammogram decreased with a woman’s age and increased with the number of breast biopsies, family history of breast cancer, use of estrogen, time between mammograms, lack of comparison with previous mammograms, and her radiologist’s tendency to describe mammograms as abnormal. Depending on her own risk factors and factors related to the screening she receives, a woman’s risk of a false-positive result by her ninth mammogram was as low as 5% or as high as 100%.
Passive Smoking Exposure and Breast Cancer Mortality
The results of several studies have indicated that women exposed to environmental tobacco smoke (ETS) are at increased risk of getting or dying of breast cancer. However, this conclusion has been controversial because there is little evidence to suggest that active smoking increases the risk of breast cancer. Although several mechanistic explanations have been proposed to explain why ETS might cause breast cancer whereas mainstream smoke does not, it is also possible that limitations to the earlier studies led to incorrect conclusions. To try to settle this issue, Wartenberg et al. (p. 1666) carried out a large, prospective cohort study of nonsmoking women in which they compared breast cancer death rates among women married to smokers with those among women married to nonsmokers. The results of this large study do not, by contrast with earlier studies, support an association between exposure to ETS and mortality from breast cancer.
"Our results could reflect the potential effects of environmental tobacco smoke on breast cancer incidence, survival, or both."
—Wartenberg et al.
Breast Cancer Resistance Protein and Topotecan
Breast cancer resistance protein (BCRP), a member of the adenosine triphosphate-binding cassette (ABC) superfamily of drug transporters, can act as a multidrug-resistance protein to render tumor cells resistant to anticancer drugs such as topotecan. Jonker et al. (p. 1651) used polarized mammalian cell lines to investigate the direction of BCRP drug transport and a BCRP inhibitor to assess how BCRP protects mice against xenobiotic drugs. They report that BCRP mediated apically directed transport of drugs in polarized cells. Also, when a BCRP inhibitor and topotecan were co-administered to wild-type mice or mutant mice lacking P-glycoprotein (another transporter sharing some BCRP substrates), the bioavailability of topotecan was higher than in control mice. The authors propose that strategic application of BCRP inhibitors may improve the effectiveness of oral chemotherapy.
In an accompanying editorial, Egorin (p. 1628) reminds us that ABC proteins are inherent components of many cells and organisms, and they play a role in maintaining cellular homeostasis and tissue integrity and in protecting against a wide range of potentially damaging compounds. He stresses that the inherent role of ABC proteins must be considered when designing therapeutic approaches directed against these molecules to avoid unintended consequences.
CYP17 Gene Polymorphism and Breast Cancer
A specific T to C nucleotide polymorphism in the 5N promoter region of the CYP17 gene has been shown to be associated with altered steroid hormone levels and therefore may influence breast cancer risk. Spurdle et al. (p. 1674) conducted a population-based, case–control family study in Australia to assess the relationship between the CYP17 promoter polymorphism and breast cancer in women younger than 40 years. The TC genotype was not associated with increased risk of breast cancer when compared with the homozygous TT genotype. However, the homozygous CC genotype was associated with increased risk when compared with the TT genotype or the TT and TC genotypes combined. Case subjects with the CC genotype and a family history of breast cancer had a threefold to fourfold higher risk of breast cancer compared with women of other groups defined by genotype and family history. The authors conclude that the CC genotype may modify the effect of other familial risk factors for early-onset breast cancer.
"Our data suggest that the CYP17 CC genotype may be implicated in early-onset familial breast cancer."
—Spurdle et al.
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