© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 19, 1433,
October 3, 2001
© 2001 Oxford University Press
IN THIS ISSUE |
Jordan et al. (p. 1449) reviewed the status of knowledge of selective estrogen receptor modulation. They pointed out that the laboratory studies so far have resulted in the development of two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, for clinical application in healthy women. These SERMs have antiestrogenic effects in the breast tissue but have estrogen-like activity in the bones and in reducing blood cholesterol levels. SERMs have different estrogen-like effects in the uterus. Tamoxifen is specifically used to reduce the incidence of breast cancer in high-risk premenopausal and postmenopausal women. In contrast, raloxifene is specifically used to reduce the risk of osteoporosis in high-risk postmenopausal women. The authors conclude that an understanding of the targeted actions of this novel drug group will potentially result in the introduction of new multifunctional medicines with applications for prevention or treatment of breast and endometrial cancers, coronary heart disease, and osteoporosis.
DNA Repair Mechanisms and Resistance to Nitrogen Mustards
Resistance to the nitrogen mustard family of DNA-alkylating antitumor agents is thought to be associated with decreased formation of and/or increased removal of DNA interstrand cross-links. Two major DNA repair pathways may be involved in repairing interstrand cross-links, homologous recombination and nonhomologous DNA endjoining. Wang et al. (p. 1473) investigated whether either mechanism was involved in epithelial tumor cell line resistance to the nitrogen mustard melphalan. The authors correlated the expression or activity of a series of proteins involved in either homologous recombination (including the Rad51-related proteins Xrcc2, Xrcc3, and Rad52) or nonhomologous DNA endjoining (including DNA-dependent protein kinase and Ku proteins) with resistance to melphalan. The authors suggest that homologous recombinational repair is involved in resistance to melphalan because only Xrcc3 levels and the density of melphalan-induced nuclear Rad51 foci, which represent sites of homologous recombinational repair, correlated with resistance to this nitrogen mustard.
In an editorial, Fojo (p. 1434) discusses the importance of DNA damage and DNA repair mechanisms as they relate to sensitivity to chemotherapy and whether DNA repair pathways could be effectively modulated as a therapeutic anticancer strategy.
Familial Multiple Myeloma
The etiology of multiple myeloma remains obscure, but reports of familial clustering of multiple myeloma suggest the involvement of environmental or host susceptibility factors. Lynch et al. (p. 1479) described the medical histories of members of one such family prone to multiple myeloma. The authors developed a pedigree for the family and characterized the clinical and genetic features of affected family members. The authors found that a sibship of seven within this family included three individuals with histologically verified multiple myeloma and two individuals with a monoclonal gammopathy of unknown significance. Other family members had acute lymphocytic leukemia, malignant melanoma, and prostate cancer. Although one affected individual had an acquired chromosomal translocation commonly linked to multiple myeloma, there were no apparent congenital chromosomal abnormalities. The authors conclude that studies of familial multiple myeloma may provide insights into its pathogenesis and, ultimately, its control and prevention.
Lung Cancer Modifier Genes
Numerous low-penetrance genes control susceptibility to cancer in experimental animals, but comprehensive information on their number and their interactions is unavailable. Tripodis et al. (p. 1484) performed a systematic search on roughly half of the mouse genome for lung tumor susceptibility (Sluc) genes that affect tumor size. Hybrid (recombinant congenic [RC]) mice were used in which a small portion of the genome was derived from a strain resistant to lung cancer, and the rest was derived from a susceptible strain. The researchers tested F2 hybrids from five crosses between the hybrid RC mice and the susceptible strain. Pregnant mice were treated with a carcinogen that induces lung tumors in mice. The size of lung tumors in the offspring was measured to estimate the influence of genes and their interactions. The researchers detected a total of 30 Sluc loci and 25 two-way interactions in the mouse genome tested and concluded that the use of appropriate mapping strategies can identify a large number of responsible loci and reveal their interactions.
Methylation in Coding Regions
Many cancers exhibit stretches of DNA that have been altered by the addition of methyl groups. Although the significance of methylation is not always certain, it often occurs in control (promoter) regions of genes involved in cell division and can interfere with or silence their function. Nguyen et al. (p. 1465) examined whether coding regions of cancer-related genes can also be methylated. They studied DNA from several regions of cancer-related genes in tumor samples from patients with leukemia and colorectal cancer and in normal tissue from the same patients. They found methylation in the coding regions of the genes from tumor samples, but methylation was reduced or absent in normal tissue. They found limited methylation in the genes’ promoter regions in tumors. In addition, different methylation patterns were found in the leukemia and colon cancer samples. Although the study was not prospective, the authors suggest that the methylation of DNA in noncontrol regions of genes may spread to promoter regions.
Prostasin, a Potential Serum Marker for Ovarian Cancer
Because ovarian cancer is often discovered at a rather late stage, screening biomarkers are needed. Mok et al. (p. 1458) used microarray technology to identify genes for secretory proteins that are overexpressed by ovarian cancer cells compared with normal ovarian cells. They selected prostasin, a serine protease, normally secreted by the prostate gland, for further study. They found that levels of serum prostasin in patients with ovarian cancer were almost double those in control subjects. Postoperative levels of serum prostasin were lower than preoperative levels in the same patient. The authors urge that prostasin should be investigated further as a screening tool or tumor marker.
In an editorial, Mills et al. (p. 1437) explain why biomarkers for ovarian cancer are important and discuss the sensitivity, specificity, and positive predictive value that are necessary for an effective screening test for ovarian cancer. They conclude by presenting the five-phase criteria for development and evaluation of biomarkers put forth by the Early Detection Research Network of the National Cancer Institute.
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