© 2004 by Oxford University Press
© 2004 Oxford University Press
IN THIS ISSUE |
-Carotene and Retinol Efficacy Trial Follow-Up
The -Carotene and Retinol Efficacy Trial, a randomized trial that
tested the effect of daily -carotene and retinyl palmitate supplements
on the incidence of lung cancer, other cancers, and death in participants who
were at high risk for lung cancer because of a history of smoking or asbestos
exposure, was stopped ahead of schedule because of a higher incidence of lung
cancer, all-cause mortality, and cardiovascular disease mortality in the
intervention arm. Goodman et al. (p.
1743) found that, 6
years after the discontinuation of the active intervention, participants who
had received the supplements still had a slightly higher incidence of lung
cancer and all-cause mortality than participants who had received placebo,
that the incidence of cardiovascular disease mortality was the same in the two
groups, and that the excess risks of lung cancer and cardiovascular disease
mortality were restricted primarily to females and to females and former
smokers, respectively.
In an editorial, Duffield-Lillico and Begg (p.
1729) discuss these
findings in the context of other prevention trials of -carotene, one of
which also reported adverse effects of -carotene supplement use on lung
cancer incidence in smokers. They also discuss the possibility that the
adverse effects of -carotene may be related to the pharmacologic doses
used and the resulting supra-physiology serum concentrations of
-carotene.
Raloxifene and Breast Cancer
The randomized, double-blind Multiple Outcomes of Raloxifene Evaluation (MORE) trial found that 4 years of raloxifene therapy decreased the risk of invasive breast cancer among postmenopausal osteoporotic women by 72%. Martino et al. (p. 1751) conducted the Continuing Outcomes Relevant to Evista (CORE) trial to examine the effect of 4 additional years of raloxifene therapy on the incidence of invasive breast cancer among MORE trial participants. The incidences of invasive breast cancer and of estrogen receptor (ER)-positive invasive breast cancer were reduced by 59% and 66%, respectively, in the raloxifene group compared with the placebo group during the 4 years of the CORE trial and by 66% and 76%, respectively, over the 8 years of both trials. The authors conclude that the reduction in the incidence of invasive breast cancer persists in postmenopausal osteoporotic women who continue to take raloxifene for longer than 4 years.
In an editorial, Kalidas et al. (p. 1731) discuss important remaining questions concerning preventive therapy for breast cancer, as well as study design issues that should be considered when interpreting the results. They note that, until results from ongoing chemoprevention trials—including one that directly compares tamoxifen to raloxifene—become available, tamoxifen remains the gold standard chemoprevention agent to reduce the risk of breast cancer in high-risk women who do not have osteoporosis.
Risks of Tamoxifen Treatment in African American Women
Recommendations for breast cancer therapy for African American women are primarily based on data from studies of white women. McCaskill-Stevens et al. (p. 1762) compared the effects of tamoxifen treatment on risk of contralateral breast cancer and thromboembolic events in African American and white women. Data from 13 National Surgical Adjuvant Breast and Bowel Project clinical trials were pooled for the analysis. The authors found that women of both ethnicities with estrogen receptor–positive breast cancer who took tamoxifen had a quantitatively similar reduced risk of contralateral breast cancer and an increased risk of thromboembolic events compared with those who did not take tamoxifen. In addition, women treated with tamoxifen and chemotherapy had an even higher risk of thromboembolic events.
Death Receptor Regulation and Celecoxib-Induced Apoptosis
Celecoxib, a cyclooxygenase 2 (COX-2) inhibitor, can induce apoptosis in various cancer cell lines through a mechanism that is independent of its COX-2 inhibitor activity but is otherwise uncharacterized. Liu et al. (p. 1769) investigated the mechanism of celecoxib-induced apoptosis further in human non–small-cell lung carcinoma (NSCLC) cell lines. They found that celecoxib treatment induced the expression of death receptors, particularly DR5, activated caspase cascades, increased DNA fragmentation, and decreased cell survival by a pathway involving DR5 and caspase 8. They noted that celecoxib cooperated with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to augment induction of apoptosis. The authors conclude that celecoxib appears to induce apoptosis through the extrinsic death receptor pathway.
Chlorpyrifos Exposure and Cancer Incidence
The insecticide chlorpyrifos is used widely in the United States. Although epidemiologic evidence of an association between chlorpyrifos exposure and cancer is lacking, some experimental studies have detected mutagenic effects of this insecticide. Lee et al. (p. 1781) evaluated cancer incidence in relation to chlorpyrifos exposure among participants in the Agricultural Health Study, a prospective cohort study of farmers and commercial pesticide applicators in Iowa and North Carolina. Chlorpyrifos-exposed applicators and nonexposed applicators had the same overall cancer incidence, and for most cancers analyzed there was no indication of an exposure–response relationship. However, the incidence of lung cancer increased with exposure, such that individuals in the highest quartile of chlorpyrifos exposure had twice the risk of lung cancer of those with no chlorpyrifos exposure. The authors note that, because the association with lung cancer had not been hypothesized prospectively, their results should be interpreted with caution pending confirmatory studies.
DNA Processing and Loss of p16INK4a and p19ARF
Reduced DNA repair has been associated with an increased risk of cutaneous melanoma, a UV-induced tumor, but the molecular mechanism of this association has not been established. The INK4a/ARF locus, which codes for the p16INK4a and p19ARF tumor suppressors, is often mutated in melanomas, but whether this locus is involved in DNA repair is not known. Sarkar-Agrawal et al. (p. 1790) introduced UV-damaged DNA into normal, p16INK4a mutant, and p19ARF mutant mouse fibroblast host cells and measured the ability of the cells to repair the damaged DNA. The DNA repair capacity of the mutant cells was lower than that of the normal cells. They conclude that mutation of the INK4a/ARF locus may predispose people to melanoma via reduced DNA repair in addition to loss of tumor suppressor function.
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