Annals of the New York Academy of Sciences
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Ann. N. Y. Acad. Sci. · Jun 1999
The novel Trk receptor tyrosine kinase inhibitor CEP-701 (KT-5555) exhibits antitumor efficacy against human pancreatic carcinoma (Panc1) xenograft growth and in vivo invasiveness.
The survival rate for patients with pancreatic ductal adenocarcinoma (PDAC) is among the poorest for all cancers. The factors that contribute to this poor prognosis are lack of effective early detection, high rate of metastases and a generally refractory response to available treatment modalities. The most commonly used treatment methods--chemotherapy and radiation therapy--are mainly used for symptom palliation, with surgery being the only "curative" treatment option. ⋯ A T/C value of 25% was observed for CEP-701-treated s.c. xenografts. In addition, CEP-701 administration inhibited tumor cell invasion in the s.c. tracheal xenograft model of in vivo invasiveness. Taken together, these data suggest that further studies are warranted to evaluate CEP-701 as a potential therapeutic agent in the treatment of PDAC.
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Ann. N. Y. Acad. Sci. · Jun 1999
The bed nucleus of the stria terminalis. A target site for noradrenergic actions in opiate withdrawal.
Hyperactivity of brain norepinephrine (NE) systems has long been implicated in mechanisms of opiate withdrawal (OW). However, little is known about where elevated NE may act to promote OW. Here we report that the bed nucleus of the stria terminalis (BNST), the densest NE target in the brain, is critical for NE actions in OW. (1) Many BNST neurons become Fos+ after OW. ⋯ Similar results were obtained with neurochemically selective lesions of the ventral ascending NE bundle, the pathway for A1 and A2 projections to the BNST. Similar lesions of the dorsal NE bundle of projections from the locus caeruleus had no effect on either aversive or somatic withdrawal symptoms. Together, these results indicate that beta-receptor activation in the BNST is critical for aversive withdrawal symptoms, and that A1 and A2 neurons in the medulla are the source of this critical NE.
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A variety of different isoforms of mammalian voltage-gated sodium channels have been identified. These channels can be classified into three different types. Eight type 1 isoforms have been identified in the CNS, PNS, skeletal muscle, and heart. ⋯ These channels diverge from the type 1 channels in critical regions, and have not been functionally expressed, so their significance is unknown. A single isoform identified in the PNS may represent a third class of channels, in that it diverges from both type 1 and 2 channels. The type 3 channel has not been functionally expressed.
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Ann. N. Y. Acad. Sci. · Apr 1999
ReviewMolecular and functional diversity of voltage-gated calcium channels.
The contributing roles of voltage-gated calcium channels (VGCC) to the generation of electrical signaling are well documented. VGCCs open in response to depolarization of the plasma membrane and mediate the flux of calcium into excitable cells, which further depolarizes the membrane. ⋯ The functional consequences of such interactions as well as other molecular aspects of VGCC will be discussed. Finally, although far from a final conclusion, what is currently known about the molecular composition of native calcium channels will be summarized.