Purpose: The nuclear transcription factor nuclear factor-B (NFB) and its inhibitor, IB, regulate the transcription of various genes involved in cell proliferation, adhesion, and survival. The NFB transcription factor complex plays a role in cancer development and progression through its influence on apoptosis. More recently, NFB has been shown to be activated in human and androgen-independent prostate cancer cells. To our knowledge, this is the first study demonstrating the prognostic significance of NFB immunoreactivity in prostate adenocarcinomas (PACs).Experimental Design: Using prostatectomy specimens, we performed immunohistochemical staining for NFB and IB␣ (Santa Cruz Biotechnology) on formalin-fixed, paraffin-embedded sections obtained from 136 patients with PAC. Cytoplasmic and nuclear immunoreactivity was scored for intensity and distribution, and results were correlated with preoperative serum prostate-specific antigen, tumor grade, stage, DNA ploidy (Feulgen spectroscopy), and biochemical disease recurrence.Results: Forty-nine percent of PACs overexpressed cytoplasmic NFB, and 63% showed decreased IB expression. Cytoplasmic NFB overexpression correlated with advanced tumor stage (P ‫؍‬ 0.048), aneuploidy (P ‫؍‬ 0.022), and biochemical disease recurrence (P ‫؍‬ 0.001). When we compared the means for the NFB-positive and -negative subgroups, NFB overexpression correlated with preoperative serum prostate-specific antigen (P ‫؍‬ 0.04) and DNA index (P ‫؍‬ 0.05). Fifteen percent of PACs expressed nuclear NFB, which correlated with high tumor grade (P ‫؍‬ 0.001) and advanced stage (P ‫؍‬ 0.05). Decreased IB␣ expression correlated with high tumor grade (P ‫؍‬ 0.015). On multivariate analysis, tumor stage (P ‫؍‬ 0.043) and NFB overexpression (P ‫؍‬ 0.006) were independent predictors of biochemical recurrence.Conclusion: These results support a role for NFB pathway proteins in the tumorigenesis of PACs. The findings are also consistent with reported experimental studies suggesting a new strategy of combined chemotherapy and specific NFB blockade in decreasing the rate of disease relapse.

This study quantifies previous observations of methylation in histologically negative samples and provides important assessment of field effects based on epigenetic events in cancer. These molecular approaches set the stage for consideration of such data in prospective trials for assessment of surgical margins and prediction of recurrence.

The recent clinical and commercial success of anticancer antibodies such as rituximab and trastuzumab has created great interest in antibody-based therapeutics for hematopoietic malignant neoplasms and solid tumors. Given the likelihood of lower toxic effects of antibodies that target tumor cells and have limited impact on nonmalignant bystander organs vs small molecules, the potential increased efficacy by conjugation to radioisotopes and other cellular toxins, and the ability to characterize the target with clinical laboratory diagnostics to improve the drug's clinical performance, current and future antibody therapeutics are likely to find substantial roles alone and in combination therapeutic strategies for treating patients with cancer. It also is likely that conjugation strategies will add new radiolabeled and toxin-linked products to the market to complement the recent approvals of ibritumomab tiuxetan and gemtuzumab ozogamicin. This review considers the structure of anticancer therapeutic antibodies and the techniques used to reduce their antigenicity. Efficacy and toxic effects, conjugation with isotopes and toxins, and validation of the antibody targets also are discussed. Antibodies approved by the Food and Drug Administration are described in detail, as are antibodies in late and early stages of clinical development.

The recent clinical and commercial success of anticancer antibodies, such as rituximab (Rituxan) and trastuzumab (Herceptin) has created great interest in antibody-based therapeutics for hematopoietic malignancies and solid tumors. Given the likely lower toxicity for antibodies versus small molecules, the potential increase in efficacy by conjugation to radioisotopes and other cellular toxins and the ability to characterize the target with clinical laboratory diagnostics to improve the drug's clinical performance, it is anticipated that current and future antibody therapeutics will find substantial roles alone and in combination therapy strategies for the treatment of patients with cancer. It is also likely that conjugation strategies will add new radiolabeled and toxin-linked products to the market to complement the recent approvals of ibritumomab tiuxetan (Zevalin) and gemtuzumab ozogamycin (Mylotarg). However, although there are a large number of agents in both early and later stages of clinical development, only a handful will make it through regulatory approval and become successful products. This review considers the structure of anticancer therapeutic antibodies, the techniques used to reduce their antigenicity, factors that influence efficacy and toxicity, conjugation with isotopes and toxins and antibody target validation.

The recent clinical and commercial success of anti-cancer antibodies such as rituximab, trastuzumab, cetuximab and bevacizumab has continued to foster great interest in antibody-based therapeutics for the treatment of both hematopoietic malignancies and solid tumors. Given the likely lower toxicity for antibodies which, in contrast with traditional cytotoxic small molecule drugs, target tumor cells and have a lower impact on non-malignant by-stander organs, the potential increases in efficacy associated with conjugation to radioisotopes and other cellular toxins and the ability to characterize the target with clinical laboratory diagnostics to improve the drugs clinical performance, it is anticipated that current and future antibody therapeutics will find substantial roles alone and in combination therapy strategies for the treatment of patients with cancer. A significant number of cell surface proteins, glycoproteins, receptors, enzymes and peptides have been discovered that have become targets for the treatment of advanced hormone-refractory prostate cancer. A variety of naked antibodies and antibody conjugates have currently progressed through preclinical development and are in early or more advanced stages of clinical development. Clinicians, scientists and prostate cancer patients are all keenly interested to learn whether these agents when administered alone or in combination with other hormonal-based and cytotoxic therapies will show lasting benefit for sufferers of this common disease.