摘要:

Interference with growth factor-receptor interactions may have particular relevance in efforts to intervene clinically in both autocrine and paracrine aspects of malignancy. Suramin is a synthetic anticancer agent that works, in part, by blocking the binding of growth factors to their receptors. While initial clinical trials have been encouraging, its use in clinical applications is associated with significant toxicities. Suradista is a novel sulfonated distamycin derivative that is also effective at complexing and inactivating growth factors and cytokines while remaining relatively nontoxic. The goal of this study was to compare the antineoplastic properties of suramin and Suradista. To achieve this, the effects of these compounds on growth factor induced mitogenesis in normal mouse fibroblasts and human umbilical vein endothelial cells were examined, as well as their ability to inhibit the growth of NIH/3T3 cells that had been transformed by the introduction of a fibroblast growth factor (FGF) 1 coding region (residues 1–154) fused to the signal peptide of the hst/KS3 gene (sp-hst/ KS3:FGF1–154). In each case, Suradista was more effective than suramin in inhibiting mitogenesis in normal cells, as well as the growth of the transformed cells. Furthermore, Suradista was also shown to be as effective as suramin at inhibiting the growth of sp-hst/KS3: FGF1–154-transformed NIH/3T3 xenografts grown in athymic nude mice when given at only 50% the dosage used for suramin (50 mg/kg for Suradista versus 100 mg/kg for suramin). In summary, these results indicate that novel compounds acting like suramin may be developed as effective antineoplastic agents and may also prove to be of clinical be

ISSN:0031-7012    

DOI:10.1159/000139538

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

This study compares the human plasma protein binding characteristics of MX2 and epirubicin. The binding characteristics were determined by equilibrium dialysis at various concentrations of the drugs. The binding dissociation constant (Kd),binding capacity (Bmax) and partitioning constant (Kp) were obtained by Scatchard analysis of the free and bound drugs in the dialysis compartments. Our results have demonstrated that plasma protein binds epirubicin or MX2 in an unsatura-ble appearance over the concentration up to 150µmol/l. At the same concentrations, plasma protein binds more epirubicin than MX2. The nature of the interaction may consist of two classes of specific binding, and a partitioning. The binding dissociation constants were 18 and 17.5 µmol/l for the higher binding class (Kd1) and 315.8 and 316.9 µmol/l for the lower binding class (Kd2), respectively, for epirubicin and MX2. The respective maximum binding capacities (Bmax) of plasma protein for epirubicin and MX2 were significantly different, 0.045 and 0.029 µmol/g protein for the higher binding class (Bmaxi), and 0.39 and 0.29 µmol/g protein for the lower binding class (Bmax2). The partitioning constants (Kp) were 21.5 × 10–5 and 20 × 10–5 litres/g protein for epirubicin and MX2, respectively. The results suggest that plasma protein binds epirubicin or MX2 with a similar affinity, but has less binding sites for MX2. One contributing mechanism to the difference in activity noted between epirubicin and MX2 may be changes in free drug

ISSN:0031-7012    

DOI:10.1159/000139539

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Nitric oxide (NO) released from Swiss 3T3 fibroblasts inhibited the proliferation of cultured mast cells (CMCs) on the CMCs/Swiss 3T3 fibroblast co-culture system. Swiss 3T3 fibroblasts produced NO upon treatment with recombinant interferon-γ (rIFN-γ). The production of NO was markedly increased by the co-treatment of rIFN-γ and recombinant tumor necrosis factor-α. This production was dependent on L-arginine and could be inhibited by the competitive substrate inhibitor, L-arginine analogue NG-monomethyl-L-arginine (NGMMA). In addition, the number of CMCs increased when treated with NGMMA in the co-culture system. These findings indicate that the elevated production of NO from Swiss 3T3 fibroblasts during the co-culture inhibited the proliferation of C

ISSN:0031-7012    

DOI:10.1159/000139540

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Effects of multiple administrations of cocaine and subsequent cocaine withdrawal on the activity of nitric oxide synthase (NOS) in brain regions and spinal cord of male Swiss-Webster mice were determined. Chronic administration of cocaine resulted in the development of sensitization to its locomotor activity in the mouse. Chronic administration of cocaine was associated with increases in NOS activity in cerebral cortex, cerebellum, midbrain, hypothalamus, hippocampus, amygdala and spinal cord, but NOS activity was unaffected in pons/ medulla and corpus striatum. Forty-eight hours after withdrawal from cocaine, NOS activity was increased only in the cerebral cortex. Recent studies have shown that cocaine-induced sensitization to behavioral effects can be inhibited by NOS inhibitors. The present studies provide the first evidence that chronic treatment with cocaine alters NOS activity in brain regions and spinal cord, and are consistent with behavioral studies with cocaine and NOS inhibitors.

ISSN:0031-7012    

DOI:10.1159/000139541

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Studies were designed to compare the effect of the nitric oxide inhibitor, Nω-nitro-L-arginine (L-NNA), and the novel ETB receptor antagonist, RES-701-1, on changes in blood pressure and renal blood flow induced by exogenous endothelin receptor agonists and to determine the effect of L-NNA on basal hemodynamics in conscious, chronically instrumented rats. Infusion of low (nonpressor) doses of L-NNA or RES-701-1 potentiated systemic and renal vasoconstriction induced by bolus injections of endothelin-1 or sarafotoxin 6c. Bolus intravenous injection or sustained infusion of L-NNA alone resulted in dose-dependent increases in blood pressure and decreases in renal blood flow, similar to our recently reported results with RES-701-1. Vasoconstriction induced by inhibition of nitric oxide was attenuated by SB 209670, a mixed ETa/b receptor antagonist, but not by BQ 123, an ETA receptor antagonist; neither antagonist altered basal hemodynamics. Collectively, the results indicate that: (1) endothelin plays an important role in the control of basal vascular tone by mediating both vasodilation and vasoconstriction; (2) these effects are mediated by different ETB receptor subtypes in the rat, one located on the endothelium that mediates vasodilation via the nitric oxide pathway, the other located on the vascular smooth muscle that mediates contraction

ISSN:0031-7012    

DOI:10.1159/000139542

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Previous studies have demonstrated that calcium storage and release from IP3-dependent sites in the sarcoplasmic reticulum play an important role in the contractile response of the rabbit urinary bladder to both field stimulation (mediated via neurotransmitter release) and bethanechol (direct muscarinic stimulation). In view of the importance of SERCA (see text) in urinary bladder smooth muscle function, we studied the distribution of SERCA by two methods; using Western blotting to quantitate the protein concentration and by enzyme analysis using thapsigargin to specifically inhibit SERCA. Rabbit and human samples of urinary bladder smooth muscle were homogenized and the homogenate separated into three particulate fractions by differential centrifugation: the cell wall-nuclear, mitochondrial, and microsomal. The protein concentration of these three particulate fractions was determined and the SERCA protein level quantitated by Western blotting using SERCA-2 antibodies. The calcium ATPase activity was quantitated using standard enzymatic analysis and the thapsigargin sensitivity determined. The results demonstrated that (1) the concentration of SERCA was significantly greater in the microsomal fraction than in either of the other fractions for both rabbit and human bladder smooth muscle; (2) the enzymatic activities of both total calcium-activated ATPase and thapsigargin-sensitive calcium ATPase were evenly divided among the three fractions, and (3) the enzymatic activity of both total calcium-activated ATPase and thapsigargin-sensitive calcium ATPase of the rabbit exceeded that of the human. In conclusion, the distribution of SERCA and calcium ATPase of the rabbit bladder smooth muscle was similar to that in the human bladder smooth muscle, although activities in rabbit were significantly greater than those of human tissue.

ISSN:0031-7012    

DOI:10.1159/000139543

出版商:S. Karger AG    

年代:1997

数据来源: Karger

ISSN:0031-7012    

DOI:10.1159/000139544

出版商:S. Karger AG    

年代:1997

数据来源: Karger

ISSN:0031-7012    

DOI:10.1159/000139545

出版商:S. Karger AG    

年代:1997

数据来源: Karger

ISSN:0031-7012    

DOI:10.1159/000139537

出版商:S. Karger AG    

年代:1997

数据来源: Karger