© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 23, 1731,
December 4, 2002
© 2002 Oxford University Press
IN THIS ISSUE |
The cyclooxygenase-2 (COX-2) inhibitor celecoxib is thought to act as a chemopreventive agent by sensitizing cancer cells to apoptotic signals. Another COX-2 inhibitor, rofecoxib, has the same COX-2 inhibitory potency as celecoxib but is less potent at inducing apoptosis. Zhu et al. (p. 1745) systematically modified the structures of celecoxib and rofecoxib to produce a series of compounds that were tested for their effects on the viability of human prostate cancer PC-3 cells and their ability to induce apoptosis in these cells. They found that the structural requirements for the induction of apoptosis were different from those for COX-2 inhibition. Like celecoxib, the derivatives mediated apoptosis by facilitating the dephosphorylation of the serine/threonine kinase Akt and extracellular signal-regulated kinase 2 (ERK2). The authors conclude that existing COX-2 inhibitors can be modified to create a new class of compounds that induce apoptosis in human prostate cancer cells.
In an editorial, DuBois (p. 1732) discusses the evidence that supports the role of COX-2 inhibition in NSAID-mediated apoptosis. He notes that future studies must determine the safety and efficacy of these new agents in experimental models and pre-clinical contexts.
Tumor and Nontumor EBV Promoter Differences
Viruses that destroy the host cells during replication (lytic replication) are not compatible with tumor growth. Although the Epstein-Barr virus (EBV) is associated with malignant and nonmalignant diseases, its lytic replication is predominately associated with nonmalignant diseases such as acute infectious mononucleosis or chronic active EBV infection. Gutiérrez et al. (p. 1757) investigated whether the promoter of an EBV lytic regulatory gene, BZLF1, differed among these diseases. The authors identified three polymorphic promoter sequences, two of which were detected in malignant samples: one sequence was identical to a prototypic sequence, and a second sequence was associated exclusively with type B EBV, a more lytic type of EBV. A third polymorphism was exclusively detected in all nonmalignant samples, including those from healthy individuals. The authors conclude that polymorphisms in the BZLF1 promoter are differentially distributed among malignant and nonmalignant cells and may identify EBV subtypes with various lytic activities.
In an editorial, Miller and El-Guindy (p. 1733) discuss the complexities of regulating the EBV lytic replication cycle by introducing the transcriptional components of the BZLF1 promoter. The authors discuss the implications of the study by Gutiérrez et al. and offer words of caution.
Sigmoidoscopy Screening Trial: Baseline Results
Because it generally takes many years for colorectal adenomas to develop into cancers, a single sigmoidoscopy examination at around age 60 years has been suggested to be an effective strategy for colorectal cancer screening. Several randomized controlled trials to investigate the effect of this strategy on colorectal cancer incidence and mortality have begun, and Segnan et al. (p. 1763) report the baseline results of one trial (the SCORE trial). Nearly 35,000 subjects were enrolled in the trial, of whom more than 17,000 were assigned to the screening group. Of these, nearly 10,000 individuals were examined by sigmoidoscopy (11% had distal adenomas), and more than 800 were referred for colonoscopy (16% had proximal adenomas). Fifty-four patients had colorectal cancer. The rate of serious adverse events was low. Most patients found the procedure acceptable. The authors note that the high yield of advanced lesions and early cancers is consistent with the projected effect of sigmoidoscopy screening on colorectal cancer incidence and mortality.
Oral Contraceptives and Breast Cancer Risk
Oral contraceptive use has been associated with an increase in the risk of breast cancer in young women. Women with a mutation in either of the breast cancer susceptibility genes BRCA1 or BRCA2 also have an increased risk of breast cancer. Narod et al. (p. 1773) examined the effects of oral contraceptive use in women with BRCA1 or BRCA2 mutations. The authors found that ever use of oral contraceptives was associated with a modestly increased risk of breast cancer among BRCA1 mutation carriers but not among BRCA2 mutation carriers. Furthermore, the authors found that among BRCA1 mutation carriers, women who first used oral contraceptives before 1975, who used them before age 30, or who used them for 5 or more years may have an increased risk for early-onset breast cancer. They conclude that oral contraceptives appear to be associated with increased risk of breast cancer in BRCA1 carriers but not in BRCA2 carriers, although data for BRCA2 carriers are limited.
HLA Alleles and Haplotypes and Nasopharyngeal Carcinoma
Nasopharyngeal carcinoma (NPC) occurs at a disproportionately high rate among Chinese individuals and is associated with Epstein-Barr virus. HLA polymorphisms are essential in the immune response to viruses. Hildesheim et al. (p. 1780) used high-resolution HLA genotyping in a case–control study in Taiwan to evaluate the association between HLA alleles and NPC. They observed an association between NPC and an HLA-A2 allele common among Chinese but not Caucasians, but they did not observe an association between NPC and the most common HLA-A2 allele in Caucasians. They also observed an extended haplotype among Chinese individuals that was associated with NPC. The authors conclude that the higher rates of NPC among Chinese might be partially explained by the association of NPC with an HLA-A2 allele common among Chinese but not Caucasians and the existence of extended haplotypes among Chinese that are associated with NPC.
Antitumor Activity of Sindbis Viral Vectors
Sindbis virus, a blood-borne virus transmitted by mosquitoes, has been used as a vector to efficiently express exogenous genes in vitro and in vivo and to induce apoptosis. Tseng et al. (p. 1790) determined whether a Sindbis viral vector could be used to target cancers in vivo. The authors found that tumors from mice treated with a Sindbis viral vector containing a reporter gene were statistically significantly smaller than tumors from untreated control mice. Moreover, in mice treated with the Sindbis viral vector, the smaller tumor size was associated with an increase in apoptosis and necrosis. The authors conclude that Sindbis viral vectors efficiently targeted tumors in vivo and were apparently delivered through the circulation.
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