© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 19, 1599,
October 6, 1999
© 1999 Oxford University Press
IN THIS ISSUE |
Tamoxifen is used both to treat breast cancer and to reduce breast cancer incidence among high-risk women. Tamoxifen has estrogen-like effects in the uterus and is associated with increased risk of endometrial cancer. Bernstein et al. (p. 1654) examined whether other known risk factors for endometrial cancer would alter the tamoxifen-endometrial cancer relationship. They found that tamoxifen-associated risk increases with prior use of estrogen replacement therapy. Women who are both obese and have a history of estrogen replacement therapy have an even more pronounced risk of endometrial cancer when prescribed tamoxifen.
Screening in the Elderly
Screening with a fecal occult blood test (FOBT) has been shown to reduce colorectal cancer mortality in controlled trials and was recently approved for payment by Medicare. Using Medicare's National Claims History System, Lurie and Welch (p. 1641) identified 24,246 Americans over age 65 years who received FOBT as a routine screening test at a physician visit. The investigators observed that, in the subsequent 8 months, 9.3% (93/1000) tested positive and had relevant follow-up testing. Of those 9.3%, only a third had the test procedures recommended by the American College of Physicians. The researchers caution that, with this pattern of practice, widespread FOBT screening is likely to be more costly and less effective than estimated from controlled trials.
In an editorial, Bond (p. 1602) points out that considerable educational effort is needed to educate the public about the impact of colorectal cancer and the value of screening. Primary care clinicians need to learn more about how to screen and follow-up abnormal results in their patients according to current guidelines, he says. These guidelines are intended to ensure that the clinical effectiveness of FOBT screening approximates the impressive efficacy of this method that has been demonstrated in scientific studies.
Lung Resistance-Related Protein and Multidrug Resistance
Lung resistance-related protein (LRP), the major vault protein in humans, is sometimes overexpressed in multidrug-resistant cells. (Vaults are cytoplasmic organelles composed of RNA and protein; approximately 5% of these structures are reported to associate with pore complexes in the nuclear membrane.) To determine whether LRP is directly involved in the expression of multidrug resistance, Kitazono et al. (p. 1647) inserted an LRP-specific ribozyme (an RNA that specifically cleaves the messenger RNA for LRP, thus inhibiting the synthesis of LRP) and studied its effect on multidrug resistance. They found that LRP is directly involved in multidrug resistance and has an important role in the transport of the cytotoxic drug Adriamycin from the nucleus to the cytoplasm.
In an accompanying editorial, Dalton and Scheper (p. 1604) discuss the possible causal relationship between LRP expression and drug resistance and point out that, although currently there is no evidence that vaults actually transport or actually bind drugs, the results of Kitazono et al. are provocative and should stimulate additional research by other investigators using similar approaches.
Prostate-Specific Antigen and Proliferation of Prostatic Stromal Cells
Prostate-specific antigen (PSA) is a serine protease that can cleave insulin-like growth factor-binding protein-3 (IGFBP3) to decrease its affinity for insulin-like growth factor-I (IGF-I). Dissociation of the IGF-I-IGFBP3 complex renders IGF-I available to bind to its cell surface receptor and thus can stimulate cell proliferation. Sutkowski et al. (p. 1663) conducted studies to evaluate the potential for PSA to modulate the effects of IGF-I and IGFBP3 on the proliferation of human benign prostatic hyperplasia (BPH)-derived fibromuscular stromal cells in primary cultures. They observed a concentration-dependent proliferative response of BPH stromal cells to IGF-I and an inhibition of that response by IGFBP3. When stromal cells were incubated with PSA in the presence or absence of IGF-I and IGFBP3, a PSA-dependent increase in stromal cell numbers was evident. The investigators conclude that PSA can modulate the in vitro interactions between IGF-I and IGFBP3 and may play a role in the regulation of human prostatic fibromuscular cell growth.
Mutations and Cervical Cancer
Expression of human leukocyte antigen (HLA) class I molecules is frequently lost in cancers. Direct in vivo evidence for mutations in HLA class I genes has been lacking. In this issue, Koopman et al. (p. 1669) have used several polymerase chain reaction-based tests to identify HLA class I gene mutations in two cell lines derived from cervical carcinomas. They found that each cell line carried a different mutation in HLA class I genes that led to the loss of the relevant allelic expression and identified the same mutation in the corresponding parental tumor. These mutations may permit the tumor cells to escape from cytotoxic T cells that specifically kill cells expressing a certain type of HLA class I protein.
Matrix Metalloproteinase Inhibitors
Matrix metalloproteinases contribute to tumor invasion and metastasis. Several synthetic inhibitors of these proteins have been designed for clinical application to prevent metastasis. FasL, a transmembrane protein that induces apoptosis (programmed cell death), is cleaved by a metalloproteinase, thereby releasing soluble FasL and inhibiting apoptosis. Mitsiades et al. (p. 1678) tested whether matrix metalloproteinase inhibitors can lead to apoptosis in the Ewing's sarcoma family tumor cell lines by protecting the transmembrane FasL from cleavage by the metalloproteinases. They found that the metalloproteinase inhibitors caused accumulation of transmembrane FasL and induced apoptosis. Ewing's sarcoma cells treated with metalloproteinase inhibitors were sensitized to doxorubicin-induced apoptosis, suggesting a possible clinical use for metalloproteinase inhibitors in combination with standard apoptosis- inducing chemotherapy.
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