© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 13, 1093,
July 7, 1999
© 1999 Oxford University Press
IN THIS ISSUE |
Studies indicate that sensitivity to mutagens is increased in patients with environmentally related cancers. This sensitivity can be evaluated by treating an individual's lymphocytes in culture with bleomycin and counting the resulting number of chromatid breaks. In combination with exposure to carcinogenic assaults, this sensitivity greatly influences cancer risk assessment, suggesting that it is a cancer susceptibility factor. Cloos et al. (p. 1125) studied the heritability of the susceptibility to DNA damage by evaluating chromatid breaks in the following three groups: 1) family members (siblings and offspring) of patients who had a history of head and neck cancer but who were currently recurrence free, 2) monozygotic twins, and 3) dizygotic twins and siblings. According to the authors, their finding of a high heritability estimate of 75% supports the notion that a common genetic susceptibility to DNA damage—and therefore a susceptibility to cancer—may exist in the general population.
In an accompanying editorial, Caporaso (p. 1097) suggests that mutagen sensitivity is an important indicator of susceptibility to tobacco-related cancer and may also reflect a component of constitutional capacity to repair DNA. He discusses the strengths and weaknesses of phenotypic assays, such as the measurement of mutagen sensitivity, and assays that study variants of specific genes in investigating how genes and the environment interact in the causation of cancer. In the end, he concludes that multiple, well-designed, large-scale population studies (i.e., involving thousands rather than hundreds of subjects) will be necessary to investigate such interactions properly.
4-HPR and Neuroblastoma Cells
N-(4-Hydroxyphenyl)retinamide (4-HPR or fenretinide) is toxic to a variety of cancers, probably, in part, due to its ability to induce levels of reactive oxygen species (ROS). Maurer et al. (p. 1138) investigated the effects of 4-HPR on neuroblastoma cells. Since neuroblastomas commonly relapse in bone marrow, a hypoxic tissue compartment, and many chemotherapeutic agents are antagonized by hypoxia, the investigators studied the influence of hypoxia and other factors on 4-HPR-induced cytotoxicity. They demonstrated that 4-HPR increased intracellular levels of ROS and ceramide (a cellular "second messenger" involved in regulating apoptosis [programmed cell death]) in these cells and that the observed cytotoxicity was due to both apoptosis and necrosis. Furthermore, 4-HPR did not affect p53 protein expression. These results suggest that 4-HPR may work through a novel, p53-independent mechanism that increases intracellular ROS and ceramide levels and that retains cytotoxic ability in hypoxic conditions.
In an editorial, Reed (p. 1099) expresses the need for understanding the primary target of 4-HPR. He believes that such information will assist in developing new analogues with greater potency and perhaps fewer side effects. Therefore, more research is needed to understand how 4-HPR influences pathways involved in the regulation of cell death in cancers, he says. He recommends incorporation of informative laboratory studies into clinical trials involving 4-HPR so that more can be learned about the molecular effects of this compound on human tumor cells in vivo.
Hormone Replacement Therapy and Endometrial Cancer
Unopposed estrogen replacement therapy (i.e., estrogen without the addition of progestins) is associated with increased risk of endometrial cancer. Since the safety profiles of combined estrogen-progestin regimens currently in use had not been clearly defined, Weiderpass et al. (p. 1131) conducted a population-based case-control study of postmenopausal women in Sweden to evaluate the endometrial cancer risk associated with use of these regimens. The investigators found that estrogen alone was associated with a strong dose- and duration-dependent increase in risk of endometrial cancer. However, the addition of progestins in a cyclical manner (i.e., mostly 10 days per cycle) was associated with a substantially lower risk. Women who used progestins continuously appeared to have a lower risk than women who used no hormone replacement therapy.
Abdominal Obesity and Risk of Colorectal Cancer
Being overweight, particularly if the excess weight represents an elevated level of adipose tissue in the abdomen, has been linked to colorectal cancer. Because abdominal obesity has been associated with increased levels of insulin in the blood and because insulin is known to be a growth factor for colon cells, Schoen et al. (p. 1147) collected data to determine whether waist circumference, as an indirect measure of visceral adipose tissue, and the metabolic effects associated with such tissue are related to the risk of colorectal cancer. Using the 5849 participants in the ongoing Cardiovascular Health Study, the researchers found statistically significant associations between the risk of colorectal cancer and fasting glucose and insulin levels, glucose and insulin levels after a 2-hour glucose challenge, and waist circumference. According to the researchers, these findings suggest that abdominal obesity and its associated metabolic effects influence the development of colorectal cancer.
A Prognostic Marker in Hepatocellular Carcinoma
The protein p73 is the first identified homologue of the tumor suppressor protein p53 and acts in a p53-like manner in inhibiting cell growth through the induction of apoptosis. To understand the role of this protein in tumor development, Tannapfel et al. (p. 1154) investigated p73 expression in the liver tissue of patients with hepatocellular carcinoma treated by surgical resection. They found that the protein was detected in 61 (32%) of 193 carcinomas examined by immunohistochemical analysis. Patients with tumors expressing p73 had shorter survival than patients whose tumors had no detectable p73 protein. The authors conclude that p73 could serve as a useful prognostic indicator in patients with hepatocellular carcinoma.
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