© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 23, 1861,
December 6, 2000
© 2000 Oxford University Press
IN THIS ISSUE |
Increased expression of the receptor tyrosine kinase Her-2-neu is associated with poor prognosis for women with breast or ovarian cancer; however, the association between Her-2-neu expression and prostate cancer has been controversial. Signoretti et al. (p. 1918) evaluated expression of Her-2-neu in untreated, androgen-dependent, and androgen-independent human prostate cancers. Although the Her-2-neu gene was not amplified in prostate cancer, the authors reported that the proportion of tumors expressing Her-2-neu protein was lowest in the untreated cancers, higher in androgen-dependent cancers, and highest in the androgen-independent cancers. The authors suggest that Her-2-neu may have a dual role in the development of prostate cancer, initially functioning in survival in an androgen-deficient environment and then having an additional, although unknown, role in androgen-independent proliferation.
In an accompanying editorial, Scher (p. 1866) notes that the available data point to but have yet to define a clear functional role for Her-2-neu in prostate cancer. Stressing that different Her-2-neu expression patterns are associated with different disease stages, he discusses the validity of Her-2-neu as a target for therapy in prostate cancer.
Chemoprevention of Gastric Dysplasia in Colombia
Scientific consensus has emerged that infection with Helicobacter pylori, a common bacterium, is a cause of gastric cancer. Meanwhile, observational studies strongly suggest a protective effect of fruit and vegetable consumption against the disease. In a rural population in Colombia, where gastric cancer is common, Correa et al. (p. 1881) randomly assigned subjects diagnosed with precancerous gastric lesions to receive various combinations of 
-carotene, ascorbic acid (both of them found in fruits and vegetables), treatment for H. pylori, and placebo. The goal of the study was to determine whether vitamin C, -carotene, and anti-H. pylori treatments could halt or reverse progression of gastric lesions. The authors found that each treatment, and particularly curing the H. pylori infection, increased the rate of regression of the gastric lesions. They conclude that dietary supplementation and cure of H. pylori infection could be effective strategies for preventing gastric cancer, especially in high-risk populations.
In an accompanying editorial, Blot (p. 1868) elaborates on aspects of the design of the randomized study. In particular, he explains how the study’s factorial design allowed for assessment of potential interactions and of treatment effects. He cautions that, while encouraging, the findings require replication before chemopreventive effects can be considered confirmed.
Cigarette Smoking and Colorectal Cancer Mortality
Whether the association between long-term cigarette smoking and an increased risk of colorectal cancer is causal or due to confounding is unknown. Chao et al. (p. 1888) sought to answer this by evaluating smoking duration and recency in a prospective nationwide mortality study (Cancer Prevention Study II) of adults aged 30 years or older. Multivariate-adjusted colorectal cancer mortality rates were highest among current smokers, were intermediate among former smokers, and were lowest in lifelong nonsmokers. Increased risk was evident after 20 or more years of smoking for men and women combined compared with never smokers. Risk among current and former smokers increased with duration of smoking and average number of cigarettes smoked per day; risk in former smokers decreased significantly with years since quitting. The authors conclude that long-term cigarette smoking is associated with increased risk of colorectal cancer mortality in both men and women.
"The precise and internally consistent risk estimates derived from this large prospective study support reconsidering the classification of colorectal cancer as, in part, a smoking-related cancer."
—Chao et al.
Synergistic Cytotoxicity in Solid Tumor Cell Lines
Maurer et al. previously reported that N-(4-hydroxyphenyl)retinamide (4-HPR, fenretinide) treatment increases ceramide levels in neuroblastoma cell lines and induces cell death. The authors extended the study (p. 1897) to determine if molecules that inhibit enzymes involved in ceramide metabolism—safingol, PPMP, and tamoxifen—enhanced 4-HPR-mediated cytotoxicity and/or affected ceramide levels. They showed that safingol was incorporated into a stereochemical variant of ceramide and synergized with 4-HPR (3:1 molar ratio) to produce a 100-fold to 10 000-fold increase in cytotoxicity relative to 4-HPR alone in cell lines derived from a variety of solid tumors. The 4-HPR and safingol combination was cytotoxic in low-oxygen conditions and was minimally toxic to normal cells tested. Addition of agents that retard ceramide glucosylation and/or acylation, such as PPMP or tamoxifen, to 4-HPR or to a 4-HPR/safingol combination further increased the cytotoxicity. The authors speculate that combinations of 4-HPR and modulators of ceramide metabolism may form the basis for a novel chemotherapy.
Breast Cancer and Tamoxifen Resistance
Many women diagnosed with breast cancer will be treated with the antiestrogen tamoxifen but will eventually develop tamoxifen-resistant disease. Previous studies indicate that one form of tamoxifen resistance is the ability of tumor cells to be stimulated rather than inhibited by prolonged treatment with tamoxifen. Schiff et al. (p. 1926) developed a mouse model to explore the molecular mechanisms responsible for this recurrent cancer growth. The authors report that prolonged tamoxifen treatment induces oxidative stress, which is associated with the activation of several stress-related signaling proteins. In turn, these proteins are associated with an increase in the activity of transcription factors that promote proliferation. The authors believe that understanding the mechanisms of tamoxifen resistance could provide insight for new strategies to prevent or delay the important clinical problem of cancer recurrence.
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