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View the Table of Contents for the March 2007 issue of Molecular Cancer Therapeutics
Page 844
The use of multivalent antibodies or fragments against tumor antigens has generated a great deal of interest. Various cellular signals, including the induction of apoptosis, inhibition of cell growth/survival, or internalization of the surface molecules, can be triggered or enhanced upon extensive cross-linking of the target/antibody complex by the multivalent form of the antibody. The goal of the studies reported here by Chiu et al. was to develop multivalent antibody constructs via grafting of antibody molecules onto liposome membranes to enhance antibody activity. Potent in vivo anti-tumor activity was demonstrated for liposomal trastuzumab. The data demonstrated the potential of liposome technology to enhance the therapeutic effect of antibodies via a mechanism that modulates cell survival through clustering of the target/antibody complex.
Page 957
Pancreatic cancer is a lethal disease, for which conventional chemo-radiation therapies have minimal effect on survival. Overexpression of a family of Inhibitor of Apoptosis (IAP) proteins is commonly observed in pancreatic malignancies. Karikari et al. determined the therapeutic efficacy of recently described small molecule antagonists of the X-linked IAP protein (XIAP) in preclinical models of pancreatic cancer. Their results confirmed that pharmacologic inhibition of XIAP is a potent therapeutic modality in pancreatic cancers. These antagonists are independently capable of inducing pancreatic cancer cell death, and also demonstrate synergy when combined with pro-apoptotic ligands, with radiation, and with a conventional anti-metabolite, gemcitabine. These preclinical results suggested that in pancreatic cancers targeting of the apoptotic machinery with XAntags is a promising therapeutic option warranting further evaluation.
Page 1013
Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, has been shown to induce phase 2 detoxication enzymes and inhibit the growth of chemically induced mammary tumors in rats. The exact mechanisms of action of SFN are not understood. In this study, Tracy et al. evaluate the effects of SFN on cell growth and death in several human breast cancer cell lines and examine the hypothesis that SFN acts as an HDAC inhibitor in these cell lines. The data suggest that SFN inhibits cell growth, activates apoptosis, inhibits HDAC activity, and decreases the expression of key proteins involved in breast cancer proliferation in human breast cancer cells. These results support testing SFN in vivo and warrant future studies examining the clinical potential of SFN in human breast cancer.
Page 1031
Doxorubicin is an effective drug against breast cancer, but is often associated with severe toxicity. By treating MCF-7 human breast cancer cells with a combination of doxorubicin and selenium, Li et al. produced a brisk enhancement of apoptosis. The authors examined the modulation of phospho-Akt and Akt targets by doxorubicin and selenium independently and in combination, and concluded that selenium repression of Akt signaling is crucial to achieving synergy. Akt may be only one of many molecular switches which can be turned on or off by selenium in facilitating a commitment to apoptosis. These pleiotrophic effects of selenium make it unique as a chemotherapeutic modulator.