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Disposition in mice of 7-hydroxystaurosporine, a protein kinase inhibitor with antitumor activity (1994)

Hill, D. L. ; Tillery, Kathleen F. ; Rose, Lucy M. ; [et al.]

Springer

Cancer chemotherapy and pharmacology 35 (1994), S. 89-92

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ISSN: 1432-0843

Keywords: Key words Disposition ; 7-Hydroxystaurosporine ; Protein kinase

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract UCN-01, a hydroxylated derivative of staurosporine, was selected for study because of its promising antitumor activity. For mice dosed intravenously, subcutaneously, or by oral gavage with this compound, the maximum tolerated doses (MTD) were 20, 10, and 〉100 mg/kg, respectively. UCN-01 was stable in mouse and dog plasma, but in human plasma it was converted to a metabolite in a process not inhibited by standard protease and esterase inhibitors. Following an intravenous dose of 10 mg/kg UCN-01, the half-lives for the initial (t 1/2α) and terminal (t 1/2β) exponential phases of elimination were 10 and 85 min, respectively; the area under the plasma concentration-time curve (AUC value) was 117 μg min ml–1. In mice dosed by oral gavage with 10 mg/kg, the calculated value for the half-life of the elimination phase was 150 min. The AUC value was 15 μg min ml–1, giving a value for bioavailability of 13%. After subcutaneous dosing with 10 mg/kg, the calculated values for half-lives for the distribution and elimination phases were 23 and 130 min, respectively; the AUC value was 113 μg min ml–1. Since this value is equivalent to that obtained for intravenous dosing, administration of UCN-01 by the subcutaneous route may be an alternative to intravenous dosing in preclinical and clinical trials.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00686290

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Interactive effects of nutrients and hormones on the expression of insulin-like growth factor binding protein-1 (IGFBP-1) mRNA and peptide, and IGF I release from isolated adult rat hepatocytes (1993)

Arany, E. ; Strain, A. J. ; Hube, M. J. ; [et al.]

New York, NY [u.a.] : Wiley-Blackwell

Journal of Cellular Physiology 155 (1993), S. 426-435

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ISSN: 0021-9541

Keywords: Life and Medical Sciences ; Cell & Developmental Biology

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Biology , Medicine

Notes: Isolated adult rat hepatocytes were used to investigate and compare the actions of glucose or amino acids and insulin, glucagon, growth hormone, and dexamethasone on the expression of insulin-like growth factor binding protein (IGFBP) mRNA, or the release of IGFBP and IGF peptides in vitro. Ligand blot analysis of culture medium conditioned for 24 h by monolayers of hepatocytes in the presence of 6.5 mM glucose revealed two species of IGFBPs, and abundant form of 30-32 kDa and a minor species of 22-24 kDa. Western blotting showed that two IGFBPs of 29-30 and 32 kDa were recognized by antiserum against hIGFBP-1, whereas hepatocytes contained a 1.6 kb transcript on Northern blot with a rat IGFBP-1 cDNA. Insulin-like growth factor BP-2 mRNA was not detected in hepatocytes and IGFBP-2 immunoreactive peptide not present in conditioned medium. The release of IGFBP-1, determined by ligand blot, was independent of gucose concentration over the range of 2.7 mM-11.1 mM, but IGFBP-1 mRNA was decreased following incubation with 6.5 mM gucose compared with 2.7 mM glucose. The release of IGFBP-1 by hepatocytes was inhibited by insulin (10nM-1μM), as was mRNA abundance. However, these effects of insulin on IGFBP-1 diminished with increasing glucose concentration. Increasing concentrations of total amino acids increased IGFBP-1 release as did dexamethasone (100 pM-100nM), whereas growth hormone and gucagon were without effect. The release of IGF I was increased by insulin, growth hormone and dexamethasone but was decreased by glucagon and amino acids, whereas changes in glucose concentration had no effect. The results show that isolated adult rat hepatocytes release IGF I and IGFBP-1 under the interactive control of nutrients and hormones involved in metabolic homeostasis. © 1993 Wiley-Liss, Inc.

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