The structural features that contribute to the anticancer properties of cyclooxygenase-2 (COX-2) inhibitors such as celecoxib and rofecoxib can be exploited in developing new anticancer agents, according to a study in the December 4 issue of the Journal of the National Cancer Institute.
Celecoxib, which gained federal approval in 1999, has been shown to reduce the number of colon polyps in people with familial adenomatous polyposis, a condition that predisposes people to colon cancer. Researchers suspected that the chemopreventive nature of nonsteroidal anti-inflammatory drugs such as celecoxib resulted from their ability to sensitize cancer cells to cell death, or apoptosis, by blocking the COX-2 enzyme. However, more recent studies had suggested that some effects of COX-2 inhibitors on apoptosis are distinct from their effects on COX-2 inhibition. For example, rofecoxib, another COX-2 inhibitor, has the same potency as celecoxib with respect to COX-2 inhibition, but its ability to induce apoptosis is two orders of magnitude lower than that displayed by celecoxib.
Jiuxiang Zhu and Ching-Shih Chen, Ph.D., of the College of Pharmacy at The Ohio State University, Columbus, and colleagues produced a series of compounds that were derivatives of celecoxib and rofecoxib to clarify the structural basis of the discrepancy in the ability of the two COX-2 inhibitors to induce apoptosis, and to see if they could optimize the apoptosis-inducing ability of celecoxib. They found that the structural features required for apoptosis induction are indeed different from that required for COX-2 inhibition. They also found that the celecoxib-derived compounds, along with celecoxib itself, mediate apoptosis through a mechanism that is independent of COX-2 inhibition.
In an related editorial, Raymond N. DuBois, M.D., Ph.D., of Vanderbilt University Medical Center, notes that this work "is a tour-de-force in chemical synthesis," but also notes that more work must be done to test the new compounds. "New agent development is extremely important for the success of the entire field of cancer prevention," DuBois writes. "These new agents must be studied and tested in a systematic way to ensure their safety and efficacy."
Contact: Michelle Gailiun, Ohio State University Medical Center, (614) 293-6054; fax: (614) 293-3730, Gailiun.1@osu.edu
Polymorphisms May Identify Specific Disease-Causing Strains of Epstein-Barr Virus
Epstein-Barr virus (EBV), a human herpesvirus, is associated with some malignant diseases such as lymphoma and nasopharyngeal cancer, but it is primarily associated with nonmalignant diseases such as acute infectious mononucleosis or chronic active EBV infection. A study in the December 4 issue of the Journal of the National Cancer Institute suggests that, by looking at mutations in a specific promoter gene, it may be possible to identify subtypes of EBV that are most often associated with specific malignant and nonmalignant diseases.
EBV can remain dormant in a person's body. It is not clear exactly what causes EBV to switch from a latent state to lytic replication (the destruction of host cells during replication), but researchers do know that the switch from latency to lytic replication is different between the two types of EBV (dubbed A and B); type B is more lytic than type A. In addition, studies have suggested that the regulatory gene BZLF1 must be present to make the switch.
Marina I. Gutiérrez and Kishor Bhatia, Ph.D., of King Fahad National Centre for Children's Cancer and Research, Riyadh, Saudi Arabia, and colleagues investigated whether the promoter sequence of the gene BZLF1 differed among the diseases associated with EBV. The authors identified three distinct promoter sequences, two of which were detected in malignant samples: one sequence was identical to a prototypic (well-characterized) sequence, and a second sequence was associated exclusively with type B 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.
Study Examines Basis of High Rates of Nasopharyngeal Carcinoma Among Chinese
Higher rates of nasopharyngeal carcinoma (NPC) among Chinese people may be partially explained by the association of NPC with an allele common among Chinese but not among Caucasians and by the existence of extended haplotypes that are associated with NPC, according to a study in the December 4 Journal of the National Cancer Institute.
NPC occurs at a disproportionately high rate among Chinese individuals, and it is associated with Epstein-Barr virus. Effective immune responses to viruses require the presence of human leukotype antigen molecules (HLAs). Because HLA molecules are highly polymorphic, Allan Hildesheim, Ph.D., of the National Cancer Institute, and his colleagues 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 a specific 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. "In summary," the authors write, "results from our study support a role of specific HLA alleles and extended haplotypes in the development of NPC."
Contact: NCI Office of Communications, (301) 496-6641, ncipressofficers@mail.nih.gov.
Sindbis Virus May Be An Effective Vector to Target Tumors
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 cell death by the mechanism known as apoptosis. Jen-Chieh Tseng, Daniel Meruelo, Ph.D., and colleagues at the New York University Cancer Institute, New York, studied 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 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 cell death rate. The authors noted that the vector could be delivered through the bloodstream and was more effective in mice with an intact immune system. Their findings are reported in the December 4 issue of the Journal of the National Cancer Institute.
Contact: Marjorie Shaffer, New York University Medical Center, (212) 404-3555, Marjorie.shaffer@med.nyu.edu
Journal
JNCI Journal of the National Cancer Institute