ErbB2 is a ligand-less member of the ErbB receptor family that functions as a coreceptor with EGFR, ErbB3, and ErbB4. Here, we describe an approach to target ErbB2's role as a coreceptor using a monoclonal antibody, 2C4, which sterically hinders ErbB2's recruitment into ErbB ligand complexes. Inhibition of ligand-dependent ErbB2 signaling by 2C4 occurs in both low- and high-ErbB2-expressing systems. Since the ErbB3 receptor contains an inactive tyrosine kinase domain, 2C4 is very effective in blocking heregulin-mediated ErbB3-ErbB2 signaling. We demonstrate that the in vitro and in vivo growth of several breast and prostate tumor models is inhibited by 2C4 treatment.

Neuronal injury in ischemic stroke is partly mediated by cytotoxic reactive oxygen species. Although the antioxidant ascorbic acid (AA) or vitamin C does not penetrate the blood-brain barrier (BBB), its oxidized form, dehydroascorbic acid (DHA), enters the brain by means of facilitative transport. We hypothesized that i.v. DHA would improve outcome after stroke because of its ability to cross the BBB and augment brain antioxidant levels. Reversible or permanent focal cerebral ischemia was created by intraluminal middle cerebral artery occlusion in mice treated with vehicle, AA, or DHA (40, 250, or 500 mg͞kg), either before or after ischemia. Given before ischemia, DHA caused dose-dependent increases in postreperfusion cerebral blood flow, with reductions in neurological deficit and mortality. In reperfused cerebral ischemia, mean infarct volume was reduced from 53% and 59% in vehicle-and AA-treated animals, respectively, to 15% in 250 mg͞kg DHAtreated animals (P < 0.05). Similar significant reductions occurred in nonreperfused cerebral ischemia. Delayed postischemic DHA administration after 15 min or 3 h also mediated improved outcomes. DHA (250 mg͞kg or 500 mg͞kg) administered at 3 h postischemia reduced infarct volume by 6-to 9-fold, to only 5% with the highest DHA dose (P < 0.05). In contrast, AA had no effect on infarct volumes, mortality, or neurological deficits. No differences in the incidence of intracerebral hemorrhage occurred. Unlike exogenous AA, DHA confers in vivo, dose-dependent neuroprotection in reperfused and nonreperfused cerebral ischemia at clinically relevant times. As a naturally occurring interconvertible form of AA with BBB permeability, DHA represents a promising pharmacological therapy for stroke based on its effects in this model of cerebral ischemia.

Early events included a decrease in androgen receptor expression, followed by a short-term increase in expression of the p53 and p21/WAF1 proteins and a marked decrease in the Ki67 proliferative index. Mid-to-late events included progressive and sustained increases in p27 and p16 protein expression, a decrease in retinoblastoma protein expression, and an increase in the transcription factor E2F1. Changes in apoptosis (programmed cell death) were not observed at any time after androgen withdrawal. These data suggest that androgen withdrawal results in a cell stress response, in which increased p53 protein produces a cell cycle arrest, without activation of p53-mediated apoptosis. The proliferative index is further decreased through the action of the cyclin-dependent kinase inhibitors p27 and p16. Androgen-independent sublines emerged 80-400 days after androgen withdrawal, and these sublines had variable growth phenotypes but were associated with mdm2 protein overexpression and increased expression of cyclin D1. These results indicate that tumor regression in this human prostate cancer model is due to cell cycle arrest rather than to apoptosis and that the emergence of androgen independence is associated with a release from cell cycle arrest.