© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 1, 1,
January 2, 2002
© 2002 Oxford University Press
IN THIS ISSUE |
Metastasis of prostate cancer to the bone is associated with increased turnover of the bone matrix. Because matrix metalloproteinases (MMPs) are involved in both the normal remodeling of bone and metastasis of prostate cancer, Nemeth et al. (p. 17) investigated the role of MMP activity in prostate cancer metastasis to the bone. They used a mouse model of prostate cancer metastasis where prostate cancer cells are injected into implanted human bone fragments. They observed that inhibiting MMP activity with batimastat reduced the number of osteoclasts per millimeter of bone, prevented bone degradation, and reduced the number of proliferating cancer cells by about two-thirds. The drug was not toxic to prostate cancer cells in vitro and did not inhibit angiogenesis or apoptosis. The authors conclude that inhibition of MMP activity could disrupt the relationship between tumor growth and bone matrix turnover.
In their editorial, Bissell et al. (p. 4) note that this study is important because it addresses the treatment of tumors (albeit PC3 prostate cancer cells) in the correct context and identifies MMPs as important players in bone matrix turnover and tumor cell growth. The editorialists urge that MMP inhibitors be explored as components of future combination therapies.
Repair Gene Hypermethylation and Patient Survival
The gene encoding the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) is transcriptionally silenced by promoter hypermethylation in several human cancers, including diffuse large B-cell lymphoma (B-DLCL). MGMT promoter hypermethylation is a marker of favorable prognosis in patients with brain tumors treated with alkylating agents. In a retrospective cohort study, Esteller et al. (p. 26) analyzed MGMT promoter methylation status in tumor DNA of B-DLCL patients receiving cyclophosphamide as part of multidrug regimens. The presence of MGMT methylation was associated with a statistically significant increase in overall survival and progression-free survival. MGMT promoter hypermethylation was both independent of and stronger than established prognostic factors, such as age, disease stage, serum lactic dehydrogenase, and performance status. The authors conclude that MGMT promoter hypermethylation appears to be a useful marker for predicting survival in patients with B-DLCL treated with multidrug regimens that include cyclophosphamide.
In an editorial, Dolan and Schilsky (p. 6) note that resistance to the antitumor effects of cyclophosphamide is not likely to be mediated by MGMT, suggesting that definitive conclusions cannot be made about the association between the outcome of patients with MGMT hypermethylation and tumor sensitivity to cyclophosphamide. The editorialists suggest that the MGMT hypermethylation may be associated with other biochemical or epigenetic changes or it may be a prognostic marker that identifies a pathogenetic subset of lymphomas with a better outcome.
Oral Contraceptives and Ovarian Cancer Risk
Oral contraceptive (OC) use is associated with a reduced risk of developing ovarian cancer, but the mechanism for the risk reduction has not been well defined. Schildkraut et al. (p. 32) investigated the relationship between the progestin and estrogen potency in combination OCs and the risk of developing ovarian cancer. The study included 390 case subjects with epithelial ovarian cancer and 2865 control subjects, between 20 and 54 years of age. The authors conclude that combination OC formulations with high-progestin potency appear to be associated with a greater reduction in ovarian cancer risk than those with low-progestin potency. They suggest that the mechanisms underlying this reduction may include inhibition of ovulation and/or some direct biologic effects of the progestin.
Quality of Life in Long-Term Breast Cancer Survivors
Women with a history of breast cancer account for more than 40% of female cancer survivors, but little is known about the quality of life (QOL) experienced by such women. In this issue, Ganz et al. (p. 39) report on a follow-up study of disease-free breast cancer survivors who were, at the time of the second survey, an average of 6.3 years post diagnosis. The researchers used several instruments to measure QOL, obtaining information on physical functioning, emotional well-being, energy level, social functioning, sexual functioning, and other aspects of health and well-being. The women surveyed reported high levels of functioning and QOL. However, QOL was lower in women who had had systemic adjuvant therapy. The authors suggest that this information may be useful for clinicians helping women to make informed decisions about the choice of systemic adjuvant therapy.
TGF-
and Progestin-Induced Apoptosis
An oral contraceptive (OC) component, progestin, induces apoptosis in the primate ovarian epithelium. Rodriguez et al. (p. 50) examined the effect of progestin on the expression of transforming growth factor- (TGF-) isoforms and its relationship to ovarian epithelial apoptosis in primate ovarian tissues. Female cynomolgus macaques received diets containing no hormones, the OC Triphasil, or estrogen or progestin alone. Compared with ovaries from the control and estrogen-only-treated monkeys, the ovaries of progestin-treated monkeys showed a marked decrease in the expression of TGF-1 in the ovarian epithelium, a concomitant increase in the expression of the TGF-2/3 isoforms in the ovarian epithelium and the hilar vascular endothelium, and a marked decrease in TGF-2/3 expression in granulosa cells. The apoptotic index of the ovarian epithelium was highly associated with the change in expression from TGF-1 to TGF-2/3 induced by progestin treatment. The authors suggest a possible biologic mechanism for the association between OC use and reduced ovarian cancer risk.
Frequency of BRCA1 Dysfunction in Ovarian Cancer
Mutations in the BRCA1 gene increase a woman’s risk of ovarian cancer, one of the most common hereditary cancers in women. Because testing for BRCA1 gene mutations is cumbersome and impractical for large populations, Geisler et al. (p. 61) developed a strategy to detect various kinds of BRCA1 dysfunction that included both mutation and gene silencing. They found that 23.1% of ovarian cancers studied had BRCA1 dysfunction and that 37.2% of the cancers with loss of heterozygosity (LOH) had this dysfunction. Thus, they concluded that using LOH at the BRCA1 locus as the first step in a screening strategy of ovarian cancers appears to increase the chance of identifying tumors with BRCA1 dysfunction.
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