© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 5, 337,
March 5, 2003
© 2003 Oxford University Press
IN THIS ISSUE |
AIB1 is an estrogen receptor (ER) coactivator that, when overexpressed, can reduce the antagonist activity of tamoxifen-bound ER in breast cancer cells. AIB1 is activated by phosphorylation via signaling through the HER-2 receptor pathway. To determine whether high AIB1 expression alone or together with HER-2 reduces the effectiveness of tamoxifen, Osborne et al. (p. 353) quantified expression of AIB1 and HER-2 from breast cancer patients who either received no adjuvant therapy or adjuvant tamoxifen therapy after surgery. They found that high AIB1 expression in tumors of patients not receiving tamoxifen was associated with better prognosis and better disease-free survival (DFS). In contrast, for patients who received tamoxifen, high AIB1 expression was associated with worse DFS. Patients whose tumors expressed high levels of both AIB1 and HER-2 had worse outcomes with tamoxifen than all other patients. The authors conclude that the antitumor activity of tamoxifen in breast cancer patients may be determined, in part, by tumor levels of AIB1 and HER-2.
In an editorial, Jordan (p. 338) discusses the merits of tamoxifen in deciphering the complexities of breast cancer and provides perspective on the link between HER-2/neu expression, the ER coactivator SRC-3 (AIB1), and the ER itself in the process of tamoxifen-resistant disease.
Chemotherapy for Elderly Patients: the MILES Trial
Vinorelbine prolongs survival and improves quality of life in elderly patients with advanced non-small-cell lung cancer (NSCLC). Studies have also suggested that gemcitabine is well tolerated and effective in such patients. Gridelli et al. (p. 362) compared the effectiveness and toxicity of the combination of vinorelbine plus gemcitabine with those of each drug given alone in an open-label, randomized phase III trial of 698 elderly patients with advanced NSCLC. The authors found that, compared with each single drug, the combination treatment did not improve survival and that, although quality of life was similar across the three treatment arms, the combination treatment was more toxic than the two drugs given singly. The authors conclude that the combination of vinorelbine plus gemcitabine is not more effective than single-agent vinorelbine or gemcitabine in the treatment of elderly patients with advanced NSCLC.
In the accompanying editorial (p. 341), Bunn and Lilenbaum, drawing from a variety of analyses, discuss whether elderly patients with advanced NSCLC should be offered chemotherapy and which therapy should be recommended.
Folate and Breast Cancer Risk
Adequate folate intake may be important in the prevention of breast cancer; however, data relating plasma folate levels to breast cancer risk remain sparse. Because levels of folate and other vitamins in the plasma could potentially have important effects on breast cancer risk, Zhang et al. (p. 373) conducted a prospective, nested case–control study among women in the Nurses’ Health Study. They found that plasma folate levels were inversely, although not statistically significantly, associated with breast cancer risk and that this association was stronger in women consuming at least 15 g/day of alcohol. Plasma vitamin B6 was also inversely associated with breast cancer risk; however, vitamin B12 was associated with risk only in premenopausal women. The authors conclude that higher plasma levels of folate and vitamin B6 may reduce breast cancer risk and that achieving adequate levels of folate may be particularly important for women at high risk of developing breast cancer because of higher alcohol consumption.
Cancer Risk and Cystic Fibrosis After Organ Transplantation
Cancer in patients with cystic fibrosis (CF) has been rare, but now more patients are reaching adulthood and receiving organ transplants, which are both factors that are associated with an increased risk of cancer. Maisonneuve et al. (p. 381) used data from the Cystic Fibrosis Foundation patient registry from 1990 through 1999 to assess the risk of cancer in CF patients who had or had not undergone transplantation of a lung and/or other organs. They found an increased risk of digestive tract cancers among all CF patients, particularly for cancers of the small bowel, colon, and biliary tract. This increased risk was more pronounced for patients who had received a transplanted organ.
Induction of Antiangiogenic Activity by rt-PA and Captopril
Many antiangiogenic molecules are generated by proteolytic cleavage from larger plasma proteins. Consequently, Merchan et al. (p. 388) investigated whether they could increase the antiangiogenic activity of plasma by treatment with recombinant tissue plasminogen activator (rt-PA) and the sulfhydryl donor captopril. They found that angiogenesis in vitro was stimulated by untreated plasma but was inhibited by plasma treated with rt-PA and captopril. In vivo angiogenesis in Matrigel plugs was substantially lower in mice treated with rt-PA and captopril than in untreated control mice. They found that the antiangiogenic activity in the plasma of three cancer patients was higher after the patients were treated with rt-PA and captopril than it was before treatment. They also noted that the antiangiogenic activity of plasma was retained after the removal of angiostatin. They conclude that treatment of plasma with rt-PA and captopril induced an antiangiogenic activity that appeared to be independent of angiostatin.
DNA Methylation and Zebularine
Gene silencing by abnormal methylation of promoter regions of regulatory genes is commonly associated with cancer. Silenced tumor suppressor genes are obvious targets for reactivation by methylation inhibitors such as 5-azacytidine (5-Aza-CR), but the compound is chemically unstable and toxic and cannot be given orally. Cheng et al. (p. 399) characterized a new demethylating agent, zebularine [1-(beta-D-ribofuranosyl)-1,2-dihydropyrimidin-2-one], which is a chemically stable cytidine analog. The authors found that zebularine inhibited DNA methylation, reactivated genes previously silenced by methylation, and exhibited minimal cytotoxicity in vitro and in vivo. Moreover, by comparison with control mice, tumor volumes were statistically significantly reduced in mice treated with high-dose zebularine administered by intraperitoneal injection or by oral gavage. The authors conclude that zebularine is a stable DNA demethylating agent and the first drug able to reactivate an epigenetically silenced gene by oral administration.
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