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A series of achiral hypoxia-activated prodrugs were synthesized on the basis of the DNA cross-linking toxin of the prodrug, ifosfamide. The hypoxia-selective cytotoxicity of several of the compounds was improved over previously reported racemic mixtures of chiral bioreductive phosphoramidate prodrugs. Prodrugs activated by 2-nitroimidazole reduction(More)
Spinothalamic (ST) neurons in the C8-T5 segments of the spinal cord were examined for responses to electrical stimulation of the left thoracic vagus nerve (LTV). Seventy-one ST neurons were studied in 39 anesthetized monkeys (Macaca fascicularis). Each neuron could be excited by manipulation of its somatic field and by electrical stimulation of(More)
Background activity of spinoreticular tract neurons in the T1-T4 segments was on average inhibited 80% by electrical stimulation of nucleus raphe magnus. Nucleus raphe magnus stimulation inhibited responses of spinoreticular tract neurons to somatic input produced by touching the skin and hair (innocuous stimulus) or pinching the skin and muscle (noxious(More)
PURPOSE Tumor hypoxia underlies treatment failure and yields a more aggressive, invasive, and metastatic cancer phenotype. TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard (Br-IPM). The purpose of this study is to characterize the antitumor activity of TH-302 and investigate its selective(More)
ING-1(heMAb), a Human Engineered monoclonal antibody to epithelial cell adhesion molecule (Ep-CAM), was evaluated for its in vitro and in vivo activity. The dissociation constant of ING-1(heMAb) for binding to Ep-CAM on HT-29 human colon tumor cells was 2 to 5 nM, similar to chimeric ING-1. In antibody-dependent cellular cytotoxicity and(More)
PURPOSE Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity,(More)
Spinothalamic and spinoreticular neurons in the C8-T5 spinal segments were examined for responsiveness to occlusion of the left main, left circumflex (CX), or left anterior descending (LAD) coronary artery in monkeys and cats. Four types of cell response to occlusion were observed, as follows: 1) cell activity increased (6 responses) or decreased (1(More)
Spinothalamic tract neurons projecting to medial thalamus (M-STT cells), ventral posterior lateral nucleus (VPL) of the thalamus (L-STT cells), or both thalamic regions (LM-STT cells) were studied in 19 monkeys anesthetized with alpha-chloralose. Twenty-seven M-STT cells were antidromically activated from nucleus centralis lateralis, nucleus centrum(More)
Thirty cats were anesthetized with alpha-chloralose, paralyzed, and artificially ventilated. Extracellular unit activity was recorded from 63 spinoreticular tract (SRT) neurons in the T12-L2 segments. All cells were excited by renal nerve stimulation and had somatic receptive fields. Intrarenal injection of bradykinin (4 micrograms/kg) increased activity of(More)
A two min orthostatic stress of 30 degrees head-up tilting in alpha-chloralose anesthetized and paralyzed cats results in compensatory changes in cardiovascular parameters (systemic blood pressure, renal perfusion pressure) and renin release. The dynamics of the response leads to shifts in systemic arterial pressure characterized by 3 phases. The initial(More)