© 2005 Oxford University Press
IN THIS ISSUE |
In This Issue
Antidepressant Use and Tamoxifen MetabolismThe efficacy of tamoxifen treatment for breast cancer varies widely among women. The drug is metabolized by several cytochrome P450 (CYP) enzymes, including the CYP2D6 isoform. Some selective serotonin reuptake inhibitors (SSRIs), which are commonly prescribed to treat hot flashes in women who take tamoxifen, are known to inhibit CYP2D6. Jin et al. (p. 30) examined the effects of concomitant SSRI use and CYP2D6 genotypes on plasma concentrations of tamoxifen and its metabolites in women who were undergoing tamoxifen therapy for breast cancer. After 4 months of tamoxifen therapy, women with a CYP2D6 homozygous variant genotype or a heterozygous genotype had a lower plasma concentration of endoxifen (an active tamoxifen metabolite) than women with the homozygous wild-type genotype. Among women with the homozygous wild-type genotype, the plasma endoxifen concentration was 58% lower in women taking an SSRI than in women who were not. The authors conclude that interactions between CYP2D6 polymorphisms and some SSRIs may be associated with altered tamoxifen activity.
CRBP-I Function in Breast Epithelium
Cellular retinol-binding protein I (CRBP-I) expression is lower in cancer cells than in normal cells, and it functions in retinol storage. Retinoic acid receptor (RAR) activation induces cell differentiation. To determine the role of retinol storage, RAR activation, and CRBP-I function in the development of breast cancer, Farias et al. (p. 21) studied RAR activity, retinol storage, and cell differentiation in immortalized mouse breast epithelial cells expressing normal or mutant CRBP-I. They found that CRBP-I function was associated with cell differentiation and retinol storage and that RAR was involved. The authors also observed that, in athymic mice, breast tumors expressing normal CRBP-I regressed, whereas those that did not express CRBP-I continued to grow. The authors conclude that loss of CRBP-I function compromises RAR activity and leads to loss of cell differentiation and tumor progression.
In an editorial (p. 3), Lotan discusses the role of retinoids in normal development and carcinogenesis and summarizes the findings of Farias et al. with respect to the role of CRBP-I in retinol storage and carcinogenesis and to breast cancer, regardless of estrogen receptor status. He suggests future strategies to determine how retinoids may prevent tumor formation and growth.
VEGFR-3 and New Lymphatic Growth
Vascular endothelial growth factor receptor 3 (VEGFR-3) has an important role in embryonic and tumor lymphatic vessel formation. To better understand how VEGFR-3 functions in adult lymphatic growth, Pytowski et al. (p. 14) developed and characterized a novel mouse monoclonal antibody to VEGFR-3 and examined its effects on lymphatic vessel regeneration using a mouse model. The antibody completely blocked new lymph vessel formation, even in the presence of human tumor cells that overexpress a natural agonist of VEGFR-3, without affecting the existing lymphatic or blood vessels. The authors conclude that targeting VEGFR-3 may block new lymphatic growth in a very exclusive way.
In a related editorial, Aoki and Tosato (p. 2) discuss the known signaling pathways by which VEFGR-3 is activated and its biologic function in normal and disease processes. They also note the importance of the findings of Pytowski et al. with respect to future medical research.
Zinc Deficiency and Upper Aerodigestive Tract Cancer
Cancer of the upper aerodigestive tract (UADT), including tongue and esophagus cancer, has been associated with dietary zinc deficiency. Cyclooxygenase-2 (COX-2) is overexpressed in a variety of malignant lesions, including those of the tongue and esophagus, raising the possibility that zinc deficiency acts on these tissues by inducing COX-2 activity. Fong et al. (p. 40) investigated this possibility in a rat model of zinc deficiency-induced UADT cancer. The esophagus and tongue of zinc-deficient rats are hyperplastic and overexpress COX-2 mRNA and protein. Both COX-2 overexpression and the hyperplastic phenotype of these rats were reduced by intragastric zinc replenishment or by treatment with a COX-2 inhibitor. The finding that two different treatments that reduce COX-2 activity also reversed the phenotypic changes that accompany zinc deficiency provides evidence that increased COX-2 activity mediates the effect of zinc deficiency on UADT cancer. The authors note that their results raise the possibility of a role for zinc supplementation in prevention of UADT cancer in populations with low dietary zinc intake.
Progesterone Receptor Gene and Ovarian Cancer Risk
Altered progestin signaling may influence the risk of both breast and ovarian cancer. One variant allele of the progesterone receptor (PGR) gene, PROGINS, has been associated with an increased risk of ovarian cancer and a decreased risk of breast cancer. To investigate the association between genetic variation at the PGR locus and the risk of breast and ovarian cancer, Pearce et al. (p. 51) identified a number of single-nucleotide polymorphisms (SNPs) in the gene. They then typed these SNPs in ovarian cancer patients and control subjects from two case-control studies and in breast cancer patients and control subjects from a cohort study. Genetic variation at the PGR was indeed associated with an increased risk of ovarian cancer, although the association was not with the PROGINS allele per se but rather with two haplotypes within the PGR gene. Genetic variation in the PGR gene was not associated with an altered risk of breast cancer.
Bone Turnover Markers and Skeletal Complications
By using data available for patients assigned to the placebo arms of two phase III trials of zoledronic acid, Brown et al. (p. 59) investigated whether bone markers have prognostic value in patients with bone metastases secondary to prostate cancer and to non-small-cell lung cancer and other solid tumors. The authors found that, in each group of patients and overall, high levels of the urinary bone resorption marker N-telopeptide and the serum bone formation marker bone-specific alkaline phosphatase were associated with an increased risk of negative outcomes, including skeletal-related events, disease progression, and death. N-telopeptide levels were a stronger prognostic indicator of negative outcomes than bone-specific alkaline phosphatase levels. The authors conclude that osteolysis, as reflected by N-telopeptide levels, has a key role in the development of skeletal complications associated with solid tumor metastases to the bone.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||