© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 8, 543,
April 17, 2002
© 2002 Oxford University Press
IN THIS ISSUE |
The antitumor activity of cyclooxygenase-2 (COX-2) inhibitors may involve the inhibition of COX-2 enzyme activity and the induction of apoptosis. It is unclear, however, whether COX-2 inhibition is required for apoptosis. Song et al. (p. 585) used tetracycline-inducible COX-2 antisense clones to assess the effect of COX-2 expression on cell viability and sensitivity to apoptosis induced by COX-2 inhibitors. They also performed a structure–activity analysis of celecoxib and various celecoxib derivatives to determine their apoptotic activity on prostate cancer cells. They found that apoptosis was not induced by depletion of COX-2 in cells. From the structure–function analysis, they found no association between apoptosis induction and COX-2 inhibition. Thus, the authors could dissociate the apoptosis-inducing activity of COX-2 inhibitors from the inhibition of COX-2 enzyme activity. They conclude that this separation of activities may lead to the development of new apoptosis-inducing agents.
In an accompanying editorial Hawk et al. (p. 545) elaborate on the importance of COX-2 inhibitors as potential agents for the prevention and treatment of cancer. They say that this study underscores the biologic complexity of COX inhibition and the promiscuous activity of COX inhibitors. They note that Song et al. used relatively high concentrations of celecoxib, and the editorialists urge that additional experiments be done at clinically relevant doses in cultured cells and in animals.
Effects of Tamoxifen and Estrogen on Brain Metabolism
Concerns about the safety of using tamoxifen to reduce breast cancer risk in elderly women have come from reports that suggest a possible association between tamoxifen use and cognitive impairment and changes in brain chemistry. Ernst et al. (p. 592) measured the cerebral concentrations of the biochemical marker myo-inositol in elderly women who had received tamoxifen therapy for breast cancer and in healthy elderly women who had received estrogen as hormone replacement therapy or neither type of therapy. The authors found that women who received either tamoxifen or estrogen had lower levels of myo-inositol, both overall and specifically in their basal ganglia, than women who had received neither therapy. They also found that the basal ganglial myo-inositol concentration was inversely related to the duration of tamoxifen treatment. The authors conclude that tamoxifen may have an effect similar to that of estrogen.
In an accompanying editorial, Ganz and colleagues (p. 547) question the authors’ suggestion that their results indicate that the women who received tamoxifen and HRT derived neuroprotective benefits from those therapies. They consider several alternative explanations for the results that take into account the known physiologic effects of estrogen in women, and they predict that reliable information about the neurocognitive effects of estrogen and tamoxifen will come from several ongoing trials.
"The decreased concentration of the glial marker [myo-inositol] in women taking either tamoxifen or estrogen suggests that both drugs may be neuroprotective and may have favorable modulatory effects on aging."
—Ernst et al.
Diphtheria Toxin Fusion Protein and Glioblastoma Cells
The prognosis for patients with brain cancer is poor, and new therapies are urgently needed. Recombinant toxic proteins that specifically target tumor cells appear to be promising. Urokinase-type plasminogen activator receptor (uPAR) is expressed on the surface of glioblastoma and other tumor cells and endothelial cells. Vallera et al. (p. 597) synthesized a recombinant fusion protein DTAT containing the catalytic portion of diphtheria toxin (DT) for cell killing fused to the noninternalizing amino-terminal (AT) fragment of uPA and investigated its effectiveness in targeting uPAR-positive cells. In vitro, DTAT was highly potent and selective in killing uPAR-expressing glioblastoma cells and human umbilical vein endothelial cells. In vivo, DTAT caused regression of glioblastoma cell-induced small tumors in mice and had little effect on the histology of the kidney, liver, heart, lung, and spleen. The investigators suggest that DTAT may have potential as intracranial glioblastoma therapy.
Endogenous Sex Hormone Levels and Breast Cancer Risk
The results of previous epidemiologic studies have suggested that postmenopausal women with breast cancer had higher levels of estrogens than healthy postmenopausal women, and it has been hypothesized that high levels of endogenous sex hormones, particularly the estrogens, may increase breast cancer risk. The Endogenous Hormones and Breast Cancer Collaborative Group (p. 606) analyzed worldwide data from nine prospective studies to produce more precise estimates of such risk in postmenopausal women. They found that postmenopausal women with the highest serum concentrations of sex hormones had a roughly twofold higher risk of breast cancer than did postmenopausal women with the lowest serum concentrations of sex hormones. The authors conclude that endogenous levels of sex hormones are strongly associated with breast cancer risk.
Interleukin-6/STAT3 Signaling in Ovarian Surface Cells
Because reproductive hormones are associated with the risk for epithelial ovarian cancer, Syed et al. (p. 617) determined whether such hormones affected the activation of interleukin-6 (IL-6)/STAT3 (signal transducer and activator of transcription-3) signaling, which may be involved in ovarian cancer. They investigated the status of STAT3, IL-6, and the IL-6 receptor in normal human ovarian surface epithelial (HOSE) cells and ovarian cancer cells. They found evidence that the IL-6/STAT3 signaling pathway may mediate HOSE cell proliferation stimulated by follicle-stimulating hormone, luteinizing hormone, or estrogen. They conclude that increased expression of the IL-6 receptor and constitutive activation of STAT3 may be associated with ovarian cancer.
| ||||||||||||||||||||||||||||||||||||