© Oxford University Press 2006.
IN THIS ISSUE
Redox Modulators and Anticancer Drug ActivityMangafodipir, a contrast agent used in magnetic resonance imaging, modifies the production of reactive oxygen species in ways that could prove useful for cancer therapy. As a superoxide dismutase mimic, it catalyzes the production of hydrogen peroxide, which is toxic to cancer cells. Via its catalase and glutathione reductase activities it can protect normal cells from death induced by reactive oxygen species, whose intracellular levels increase after treatment with anticancer drugs. In this issue (p. 236), Alexandre et al. examined the effect of mangafodipir on anticancer drug activity and cytotoxicity against both normal and cancer cells. Mangafodipir protected normal leukocytes from the toxicity of several different anticancer drugs. It also reduced the incidence of paclitaxel-induced leukopenia in mice and increased the antitumor effect of this chemotherapeutic drug against implanted tumors.
In an editorial, Doroshow (p. 223) points out that our understanding of the role of reactive oxygen species has evolved with the recent recognition that hydrogen peroxide is not only a toxic byproduct of cellular metabolism but also, at low levels, a component of cell signaling. He discusses Alexandre et al.'s findings in this context, noting that the results are of interest because they suggest that some of the toxic effects of the reactive oxygen species produced in normal cells exposed to chemotherapeutic drugs can be ameliorated.
Antioxidant Vitamins and Prostate Cancer Risk
The micronutrient antioxidants vitamin E, 
-carotene, and vitamin C protect cells from oxidative damage potentially involved in prostate carcinogenesis. Supplemental vitamin E and supplemental -carotene decrease the risk of prostate cancer among some subgroups of men, but their general utility for cancer prevention remains unclear. Kirsh et al. (p. 245) evaluated the association between intakes of these micronutrient antioxidants and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. There was no overall association between prostate cancer risk and dietary or supplemental intakes of vitamin E, -carotene, or vitamin C. However, among current and recent smokers, decreasing risks of advanced prostate cancer were associated with increasing dose and duration of supplemental vitamin E use. Supplemental -carotene intake (of at least 2,000 µg/day) was associated with decreased risk in men with low dietary -carotene intake. The authors conclude that their results provide no strong support for population-wide implementation of high-dose antioxidant supplementation for prostate cancer prevention.
In an editorial, Lee et al. (p. 225) review the existing trial data regarding antioxidant intake in cancer prevention and discuss the validity of the subgroup finding in the PLCO study of a reduced risk of advanced prostate cancer among smokers and recent quitters who use supplemental vitamin E. They point out that, given the continuing uncertainty about the role of antioxidant supplementation in prostate cancer prevention among smokers, the most prudent course of action for overall cancer prevention is smoking prevention.
Gene Methylation in Tumor-Associated Normal Cells
Gene promoter methylation leads to gene silencing and occurs frequently in cancer. To investigate this mechanism in prostate cancer, Hanson et al. (p. 255) analyzed promoter methylation of the GSTP1, RAR2, and CD44 genes in prostate tumor epithelial tissue and tumor-associated stroma and in surrounding normal epithelia and stroma of five patients with prostate cancer and in prostate epithelia and stroma of five men with benign prostate hyperplasia. The GSTP1 and RAR2 promoters were methylated in prostate tumor epithelia from all five patients, in the tumor-associated stroma in four, and in the normal epithelium and stroma of some patients but not in the men without cancer. CD44 was methylated in tumor epithelium of four patients but not in the tumor-associated stroma or in any of the normal tissues. The authors conclude that these findings may lead to better understanding of prostate carcinogenesis and to new diagnostic and prognostic markers and therapeutic targets.
Breast Cancer Grade and Gene Expression Profiling
Breast tumors of histologic grade 2 have an intermediate risk of recurrence, which is not informative for clinical decision-making. Sotiriou et al. (p. 262) examined whether gene expression profiles of breast cancers could be used to improve histologic grading. They identified genes that were differentially expressed in histologic grade 1 and 3 tumors and used these expression profiles to define the gene expression grade index. Histologic grade 2 tumors with a high index value were associated with a higher recurrence risk than grade 2 tumors with a low index value. The authors conclude that reclassification of patients with histologic grade 2 tumors into two groups by use of a gene expression grade index may improve the accuracy of tumor grading and thus its prognostic value.
Darbepoetin Alfa Treatment Every 3 Weeks
Darbepoetin alfa treatment every 3 weeks would reduce the burden to patients and could be synchronized with chemotherapy. To compare the efficacy and safety of this regimen with the standard weekly treatment, Canon et al. (p. 273) conducted a randomized, double-blind, active-controlled phase 3 trial in 110 European centers using a noninferiority study design. Fewer patients in the 3-week treatment arm than in the weekly arm received red blood cell transfusions from week 5 to the end of the treatment phase. In addition, the numbers of patients in each arm who reached the target hemoglobin level were similar, as were the frequencies of thromboembolic events and the overall safety. The authors conclude that patients with chemotherapy-induced anemia can safely and effectively be treated with darbepoetin alfa given every 3 weeks.
MDM2 SNP, p53 Status, and Colorectal Cancer Onset
A single-nucleotide polymorphism (SNP) in the promoter of the MDM2 gene, SNP309 (a T
G change), leads to an increase in the level of Mdm2 protein, which causes attenuation of the p53 pathway. To examine the effect of this SNP in colorectal cancer pathogenesis, Menin et al. (p. 285) genotyped it in 153 colorectal cancer patients who were stratified according to p53 mutation status and age at diagnosis. Among the 77 patients with p53 wild-type tumors, the median age at colorectal cancer diagnosis was 71.5 years for patients with the T/T genotype and 61.0 years for patients with the T/G or G/G genotype. The authors conclude that MDM2–SNP309 modifies the age at colorectal cancer onset for patients whose tumors have a wild-type p53 gene.
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