© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 14, 1177,
July 21, 1999
© 1999 Oxford University Press
IN THIS ISSUE |
Antioxidants show promise for reducing prostate cancer risk. To understand the mechanism
of this protection, Ripple et al. (p. 1227) studied the effect of antioxidants
vitamins C and E on several male hormone (androgen)-induced changes in a human prostate
carcinoma cell line. Androgens increased both reactive oxygen species levels and the
DNA-binding activity of transcriptional activators AP-1 and NF-
B, which are sensitive to
oxidative stress. These effects were blocked by the antioxidants. The authors note that further
studies are needed to understand the pathways involving androgens, oxidative stress, and prostate
carcinogenesis and the beneficial intervention by antioxidants in these pathways.
Enhancing Antifolate Sensitivity
Antifolates are popular antitumor agents, but they are only minimally effective against slow-growing tumors and they poison actively dividing cells in normal tissues. Antifolates are potentiated within the target cells by an enzyme, folylpolyglutamyl synthetase (FPGS). Aghi et al. (p. 1233) therefore examined the response to antifolates of slow-growing gliosarcoma cells transfected with a complementary DNA (cDNA) that encodes the human FPGS protein. The researchers used rat gliosarcoma cells to test the antifolates methotrexate and edatrexate, both in culture and in an in vivo model. They found that cells transfected with FPGS cDNA were more sensitive to the drugs than were untransformed cells and that the transformed cells could increase the response of untransformed cells in mixed cultures (a bystander effect). The authors suggest that their FPGS gene-transfer technique, which uses an nonimmunogenic enzyme, merits further investigation.
". . . [T]ransfecting glioma cell lines already expressing [folylpolyglutamyl synthetase (FPGS)] with a plasmid containing the FPGS [complementary DNA] increases antifolate pulse sensitivity in culture."
—Aghi et al.
Identifying Drugs Against Human Papillomavirus
Human papillomavirus (HPV) type 16 encodes three oncoproteins—E5, E6, and E7—which play a role in HPV-mediated cellular transformation. In E6, two potential zinc-finger domains critical for the normal function of this protein have been characterized. Beerheide et al. (p. 1211) describe several assays to identify compounds capable of interfering with the binding of zinc to E6 protein. Among 36 compounds preselected on the basis of their structure as likely candidates, nine were shown to eject zinc from E6, two of the nine were shown to interfere with E6 binding to two proteins that are coactivators of E6-mediated cellular transformation, and one of the latter two selectively inhibited the viability of HPV-containing cells. The investigators conclude that the described assays may be useful in the development of drugs against cervical cancer, genital warts, and asymptomatic infections by genital HPVs.
In an editorial, Foster and Phelps (p. 1180) emphasize the need for establishing E6 as a validated target for these inhibitors and the need to establish that E6-related biochemical activities are dependent on the integrity of the zinc fingers. They further stress the importance of determining the absolute specificity of these inhibitors by examining their activities against a battery of other relevant proteins, including a series of zinc-containing metalloproteins.
Tobacco Smoke and Lung Cancer
Substantial research links specific components of tobacco smoke (which is a complex mixture of gases and particulate matter) with genetic changes in somatic cells that can lead to the development of cancer. In a review, Hecht (p. 1194) notes that 20 carcinogens found in tobacco smoke convincingly cause lung tumors in laboratory animals or humans and that a subset of these compounds—polycyclic aromatic hydrocarbons and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone—are likely to play a major role in the development of lung cancer in smokers. Focusing on these carcinogens, the author discusses the molecular mechanisms by which smoke carcinogens interact with DNA and the less well-defined relationship between specific carcinogens and changes in oncogenes and tumor suppressor genes. Hecht concludes that understanding the mechanisms of tobacco-induced cancer can lead to new approaches for lung cancer prevention.
Colorectal Cancer in Hong Kong
The number of young people (under 46 years of age) with colorectal cancer is substantially higher in Hong Kong than in many countries with predominantly Caucasian populations. To determine whether the Southern Chinese population in Hong Kong has a genetic predisposition to this disease, Chan et al. (p. 1221) investigated the incidence of microsatellite DNA instability at 10 chromosomal loci in specimens from 117 patients with this type of cancer. They found that the frequency of DNA instability varied statistically significantly with age, being present in more than 60% of those younger than 31 years at diagnosis but in only 15% of those diagnosed at age 46 years or older. In patients younger than 31 years at diagnosis, more than 80% carried germline mutations in one of three mismatch repair genes examined.
BRCA1 and BRCA2 Mutations
Warner et al. (p. 1241) have investigated the extent to which any of three specific mutations, two in the BRCA1 gene and one in the BRCA2 gene, contribute to the development of breast cancer in the Ashkenazi Jewish population. The authors tested the following groups for the three mutations: Jewish women with prevalent cases of breast cancer, non-Jewish women with breast cancer, and healthy Jewish women with no history of cancer. They found that approximately 12% of the Jewish patients carried one of the mutations, and they estimated that the consequent development of breast cancer by age 70 was approximately 60% for BRCA1 mutations and 28% for the BRCA2 mutation. The authors conclude that genetic testing may be useful when Jewish women are diagnosed with breast cancer before age 50 years or have a close relative with ovarian or early-onset breast cancer.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||