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PubMed2000

Single-unit and polygraphic recordings associated with systemic or local pharmacology: a multi-purpose stereotaxic approach for the awake, anaesthetic-free, and head-restrained rat.

In order to avoid any artifactual pharmacological interferences with anaesthetic agents, a procedure has been developed for working on the awake, anaesthetic-free rat in a head-restrained condition. It allows, on the same animal and over several consecutive days, single-unit recordings in combination with systemic or local pharmacology (microiontophoresis or micropressure ejections), as well as monitoring vigilance states via the electroencephalogram and the electromyogram. After the cementing of a special "U"-shaped device on its skull under general anaesthesia, the animal is progressively habituated to stay daily, for several hours, under a painless corresponding stereotaxic restraint. This system can be easily adapted to different stereotaxic frames and, because of its spatial flexibility for targetting the desired rostrocaudal or lateral positions, allows access to a large number of cerebral structures. Experiments performed on Globus Pallidus, Substantia Nigra, and Locus Coeruleus neurons, combining the different possibilities of this system, are reported. They demonstrate, on the awake anaesthetic-free head-restrained rat, and under suitable ethical conditions, the feasibility of single-unit recordings of identified neurons associated with the study of their pharmacological reactivity after systemic or local drug administrations without any other drug interferences, and in physiologically relevant conditions such as the spontaneous alternance of vigilance states.

Action Potentials↗
PubMed2005

Pharmacological cardioversion for atrial fibrillation and flutter.

BACKGROUND: Atrial fibrillation is the commonest cardiac dysrhythmia. It is associated with significant morbidity and mortality. There are two approaches to the management of atrial fibrillation: controlling the ventricular rate or converting to sinus rhythm in the expectation that this would abolish its adverse effects. OBJECTIVES: To assess the effects of pharmacological cardioversion of atrial fibrillation in adults on the annual risk of stroke, peripheral embolism, and mortality. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (Issue 3, 2002), MEDLINE (2000 to 2002), EMBASE (1998 to 2002), CINAHL (1982 to 2002), Web of Science (1981 to 2002). We hand searched the following journals: Circulation (1997 to 2002), Heart (1997 to 2002), European Heart Journal (1997-2002), Journal of the American College of Cardiology (1997-2002) and selected abstracts published on the web site of the North American Society of Pacing and Electrophysiology (2001, 2002). SELECTION CRITERIA: Randomised controlled trials or controlled clinical trials of pharmacological cardioversion versus rate control in adults (>18 years) with acute, paroxysmal or sustained atrial fibrillation or atrial flutter, of any duration and of any aetiology. DATA COLLECTION AND ANALYSIS: One reviewer applied the inclusion criteria and extracted the data. Trial quality was assessed and the data were entered into RevMan. MAIN RESULTS: We identified two completed studies AFFIRM (n=4060) and PIAF (n=252). We found no difference in mortality between rhythm control and rate control relative risk 1.14 (95% confidence interval 1.00 to 1.31). Both studies show significantly higher rates of hospitalisation and adverse events in the rhythm control group and no difference in quality of life between the two treatment groups. In AFFIRM there was a similar incidence of ischaemic stroke, bleeding and systemic embolism in the two groups. Certain malignant dysrhythmias were significantly more likely to occur in the rhythm control group. There were similar scores of cognitive assessment. In PIAF, cardioverted patients enjoyed an improved exercise tolerance but there was no overall benefit in terms of symptom control or quality of life. AUTHORS' CONCLUSIONS: There is no evidence that pharmacological cardioversion of atrial fibrillation to sinus rhythm is superior to rate control. Rhythm control is associated with more adverse effects and increased hospitalisation. It does not reduce the risk of stroke. The conclusions cannot be generalised to all people with atrial fibrillation. Most of the patients included in these studies were relatively older (>60 years) with significant cardiovascular risk factors.

Adult↗
PubMed2001

Structural determinants for AMPA agonist activity of aryl or heteroaryl substituted AMPA analogues. Synthesis and pharmacology.

We have previously reported the synthesis and pharmacological characterization of analogues of 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA, 1a), in which the methyl group was replaced by a phenyl group (APPA, 1b) or heteroaryl groups. While 2b and its 3-pyridyl analogue 2-amino-3-[3-hydroxy-5-(3-pyridyl)-4-isoxazolyl]propionic acid (3-Py-AMPA, 3) show very low affinity for AMPA receptors, introduction of heteroaryl substituents containing heteroatom in the 2-position provides potent AMPA receptor agonists. We here report the synthesis and pharmacology of 2-amino-3-(3-hydroxy-5-pyrazinyl-4-isoxazolyl)propionic acid (7) (IC50 = 1.2 microM), which is weaker as an AMPA agonist than AMPA (IC50 = 0.040 microM; EC50 = 3.5 microM) but comparable in potency with 2-Py-AMPA (4) (IC50 = 0.57 microM; EC50 = 7.4 microM), as determined in radioligand binding and electrophysiological experiments, respectively. The AMPA analogues 8a-c, containing 2-, 3-, or 4-methoxyphenyl substituents, respectively, and the corresponding hydroxyphenyl analogues, 9a-c, were also synthesized and evaluated pharmacologically. With the exception of 2-amino-3-[3-hydroxy-5-(2-hydroxyphenyl)-4-isoxazolyl]propionic acid (9a), which is a very weak AMPA agonist (IC50 = 45 microM; EC50 = 324 microM), none of these compounds showed detectable effect at AMPA receptors.

Animals↗
PubMed1990

Urinary incontinence: classification and pharmacological therapy.

Pharmacological therapy has been developed which can have significant impact in the management of many forms of urinary incontinence and voiding dysfunction. In general the clinical laboratory studies which have supported or challenged the efficacy of many of the commonly prescribed drugs for voiding dysfunction are often difficult to interpret and contradictory. The available clinical studies often do not demonstrate a lack of bias. Nor do they include an adequate number of subjects, use appropriate and sensitive methods of evaluation, employ double-blind placebo-controlled design, or appear statistically valid. Although the contribution of laboratory research has been of unquestionable value in the development of our current knowledge of lower urinary tract pharmacology it is difficult to interpret the results of in vitro pharmacological studies because of the array of experimental models used and the need to extrapolate to in vivo activity. This paper utilizes a functional scheme which classifies agents by their effects on urinary storage and emptying. The purpose of this review is to promote discussion of the application of uropharmacological investigation to the development of newer, more efficacious forms of drug therapy.

Estrogens↗
PubMed2003

Endogenous dopamine release after pharmacological challenges in Parkinson's disease.

Using (11)C-raclopride positron emission tomography after methamphetamine challenge, we have evaluated regional brain changes in synaptic dopamine (DA) levels in six volunteers and six advanced Parkinson's disease (PD) patients. The pharmacological challenge induced significant release of endogenous DA in putamen not only in the normal subjects, as reflected by a 25.2% reduction in (11)C-raclopride binding potential as compared with placebo, but also in the PD patients (6.8%). In individual PD patients, we found a correlation between putamen DA release and DA storage, as measured by (18)F-dopa uptake. Localization of significant changes in (11)C-raclopride binding after methamphetamine at a voxel level with statistical parametric mapping identified striatal and prefrontal DA release in both cohorts. Statistical comparisons between normal subjects and PD confirmed significantly reduced DA release in striatal areas in PD, but normal levels of prefrontal DA release. In conclusion, significant endogenous DA release can still be induced by pharmacological challenges in the putamen of advanced PD patients, and this release correlates with residual DA storage capacity. Our data also show that the capacity to release normal DA levels in prefrontal areas after a pharmacological challenge is preserved in severe stages of the disease.

Aged↗
PubMed2003

Management of depression in rheumatoid arthritis: a combined pharmacologic and cognitive-behavioral approach.

OBJECTIVE: To examine the effectiveness of cognitive-behavioral and pharmacologic treatment of depression in rheumatoid arthritis (RA). METHODS: Subjects (n = 54) with confirmed diagnoses of both major depression and RA were randomly assigned to 1 of 3 groups: 1) cognitive-behavioral/pharmacologic group (CB-PHARM), 2) attention-control/pharmacologic group, or 3) pharmacologic control group. Measures of depression, psychosocial status, health status, pain, and disease activity were collected at baseline, posttreatment (10 weeks), 6-month followup, and 15-month followup. Data were analyzed to compare the treatment effectiveness of the groups; data also were aggregated to examine the effects of antidepressive medication over time. Lastly, a no-treatment control group was defined from a cohort of persons who declined participation. RESULTS: Baseline comparisons on demographic and dependent measures revealed a need to assess covariates on age and education; baseline scores on dependent measures also were entered as covariates. Analyses of covariance revealed no statistically significant group differences at postintervention, 6-month followup, or 15-month followup, except higher state and trait anxiety scores for the CB-PHARM group at the 15-month followup. In the longitudinal analyses of the effects of antidepressive medication, significant improvement in psychological status and health status were found at posttreatment, 6-month followup, and 15-month followup, but no significant improvements were shown for pain or disease activity. In addition, the comparison of the aggregated pharmacologic group with a no-treatment group revealed a statistically significant benefit for the 3 groups that received the antidepressive medication. CONCLUSION: In persons with RA, cognitive-behavioral approaches to the management of depression were not found to be additive to antidepressant medication alone, but antidepressant intervention was superior to no treatment.

Antidepressive Agents↗
PubMed2003

Anti-pressor effects of whole body exposure to static magnetic field on pharmacologically induced hypertension in conscious rabbits.

Acute effects of whole body exposure to static magnetic field (SMF) on pharmacologically induced hypertension in a conscious rabbit were evaluated. Hypertensive and vasoconstrictive actions were induced by norepinephrine (NE) or a nonselective nitric oxide synthase (NOS) inhibitor, N(omega)-nitro-l-arginine methyl ester (l-NAME). The hemodynamics in a central artery of the ear lobe was measured continuously and analyzed by penetrating microphotoelectric plethysmography (MPPG). Concurrently, blood pressure (BP) changes in a central artery, contralateral to that of the MPPG measured ear lobe, were monitored. Magnetic flux densities were 5.5 mT (Bmax), the magnetic gradient peaked in the throat at the level of approximately 0.09 mT/mm, and the duration of exposure was 30 min. The results demonstrated that under normal physiological conditions without treatment of pharmacological agents, there were no statistically significant differences in the hemodynamics and BP changes between the sham and the SMF exposure alone. Under pharmacologically induced hypertensive conditions, the whole body exposure to nonuniform SMF with peak magnetic gradient in the carotid sinus baroreceptor significantly attenuated the vasoconstriction and suppressed the elevation of BPs. These findings suggest that antipressor effects of the SMF on the hemodynamics under NE or l-NAME induced high vascular tone might be, in part, dependent on modulation of NE mediated response in conjunction with alteration in NOS activity, thereby modulating BPs.

Animals↗
PubMed2005

Effects of neck exposure to 5.5 mT static magnetic field on pharmacologically modulated blood pressure in conscious rabbits.

Static magnetic fields (SMF) in the millitesla (mT) range have been reported to modulate microcirculatory hemodynamics and/or blood pressure (BP) under pharmacologically modified state in mammals. This study was designed to investigate the acute effects of local application of a SMF to neck or pelvic region under pharmacologically modulated BP; norepinephrine (NE)-induced hypertension as well as an L-type voltage-gated Ca(2+) channel blocker, nicardipine (NIC)-induced hypotension in conscious rabbits. Magnetic flux densities were up to 5.5 mT and the spatial magnetic gradient peaked in neck (carotid sinus baroreceptor) region at the level of approximately 0.06 mT/mm. The duration of exposure was 30 min (including 10 min of pretreatment) and the effects on BP were investigated up to 100 min postexposure. Baroreflex sensitivity (BRS) was estimated from invasive recordings of systolic BP and pulse interval. Neck exposure to 5.5 mT significantly attenuated the pharmacologically induced vasoconstriction or vasodilation, and subsequently suppressed the increase or decrease in BP compared with sham exposure. In contrast, pelvic exposure to 5.5 mT did not significantly antagonized NE-elevated BP or NIC-reduced BP. The neck exposure to 5.5 mT has a biphasic and restorative effect on vascular tone and BP acting to normalize the tone and BP. The neck exposure to 5.5 mT caused a significant increase in BRS in NE-elevated BP compared with sham exposure. The buffering effects of the SMF on increased hemodynamic variability under NE-induced high vascular tone and NIC-induced low vascular tone might be, in part, dependent on baroreflex pathways, which could modulate NE-mediated response in conjunction with Ca(2+) dynamics.

Animals↗
PubMed2004

Fallacy of thoracic side-branch steal from the internal mammary artery: analysis of left internal mammary artery coronary flow during thoracic side-branch occlusion with pharmacologic and exercise-induced hyperemia.

In some patients, myocardial ischemia after coronary artery bypass graft surgery has been attributed to a coronary steal phenomenon through a thoracic side branch originating from the left internal mammary artery (LIMA), even in the absence of subclavian or LIMA stenosis. To demonstrate that coronary flow through the LIMA is unchanged by occlusion of a LIMA side branch, we examined LIMA coronary flow velocity measurements (0.014" Doppler flow wire) in three patients at rest, during adenosine hyperemia, and again during hyperemia induced by left arm exercise before and again after the balloon occlusion of the thoracic side branch. For the three patients, no significant changes in resting or hyperemic flow were noted due to side-branch occlusion. Before side-branch occlusion, pharmacologic intra-arterial (adenosine) coronary flow reserve (hyperemic-to-basal flow velocity ratio) was 2.6, 1.5, and 3.2 and exercise flow reserve was 2.1, 1.3, and 1.2, respectively. After side-branch occlusion, pharmacologic coronary flow reserve was 2.5, 1.8, and 2.7 with exercise flow reserve of 1.8, 1.1, and 1.3, respectively. Under most ordinary circumstances, thoracic side-branch steal does not exist and that side-branch occlusion does not alter LIMA flow at rest or during pharmacologic or exercise-induced hyperemia. These data further suggest that a demonstration of the physiologic value of side-branch occlusion should precede surgical or percutaneous interruption of the thoracic artery in such patients.

Angina Pectoris↗
PubMed1988

Evaluation of left ventricular contractile performance from baseline stress-shortening data in humans: comparison with pharmacological afterload challenge.

The purpose of this study was to evaluate whether the baseline stress-shortening data reflect the contractile state adequately and give results comparable to the evaluation of the end-systolic stress-shortening relationships using pharmacological manipulation of afterload. Five groups were studied (total 152 patients): a control group of 30 healthy volunteers, 32 patients after surgical correction of infantile tetralogy of Fallot, 50 patients treated for childhood malignancies with doxorubicin, 17 patients with left ventricular hypertrophy due to systemic hypertension, and 23 patients with congestive cardiomyopathy. In all patients except those with congestive cardiomyopathy, afterload was altered pharmacologically to evaluate the individual stress-shortening relationship. In all patients the baseline stress-shortening data were evaluated, as well as their relative positions to two predefined normal ranges for the relationship between end-systolic stress and shortening. Additionally, a slope value was calculated from the baseline data of the five groups studied and compared with the data obtained by pharmacological afterload increment. Our data show that the comparison of individual baseline data of end-systolic wall stress and fractional shortening with predefined normal ranges for the relationship between end-systolic stress and shortening is inadequate. The appropriate normal range to compare with is the 95% confidence interval of baseline stress-shortening data in normal subjects. Also the calculation of a slope value from the baseline stress-shortening data of a group of patients seems to be inappropriate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Strategies for pharmacologic modulation of the heart failure phenotype.

The end-stage heart failure phenotype is characterized by marked dyspnea on exertion, edema, and overwhelming fatigue, and by a high incidence of sudden death. Patients who display the end-stage phenotype have transitioned from a normal phenotype with myocardial damage at a cellular level. This transition appears to be mediated by events at both the cellular and molecular levels. Until recently, it was generally believed that this transition was irreversible. However, recent clinical trials have demonstrated that the phenotype can be changed with pharmacologic agents. These agents have been demonstrated to improve exercise capability, increase ventricular function, and improve symptoms. Important recent studies have shown that pharmacologic agents can substantially alter the high mortality rates associated with the end-stage heart failure phenotype. As we learn more about the molecular and cellular events that initiate and support the transition from cardiac compensation to decompensation, we will be able to improve our pharmacologic targeting and, we hope, be able to delay the development of the end-stage heart failure phenotype to an even greater degree.

Adrenergic beta-Antagonists↗
PubMed2003

Pharmacologic characteristics of statins.

Considerable effort has been devoted to improving the pharmacologic characteristics and clinical effects of statins. Desirable pharmacologic properties include potent inhibition of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, selectivity of uptake in hepatocytes, low systemic bioavailability to reduce systemic adverse effects, prolonged elimination half-life, and no or minimal hepatic metabolism to avoid drug-drug interactions. The desirable effects on lipid variables would include increased effectiveness in reducing levels of low-density lipoprotein cholesterol and other atherogenic lipoproteins and measurable beneficial effects on high-density lipoprotein cholesterol levels. As a product of the ongoing efforts regarding statin pharmacology, the new statin rosuvastatin exhibits significant improvements in several of these characteristics.

Cholesterol, HDL↗
PubMed2005

Pharmacologic treatment of anorexia nervosa: where do we go from here?

Anorexia nervosa (AN) is a serious mental disorder, characterized by severely low weight and cognitive distortions about body shape and weight. AN is generally associated with a range of psychological symptoms, including depression, anxiety, obsessions, and rituals. The current study summarized findings from randomized controlled trials (RCT) using pharmacologic treatments in patients with AN. We conducted a review of literature using Medline. Several classes of pharmacologic agents have been studied in small samples of patients with acute AN without finding clear benefit to eating, weight, body shape concerns, or associated psychopathology. Studies have been limited by small sample sizes, as well as by research design with most studies adding medication to comprehensive hospital-based treatment programs. Future directions for pharmacologic treatment research in AN should include outpatient trials, rigorous study of atypical antipsychotic medication, and assessment of medication effect for relapse prevention in weight-restored patients.

Anorexia Nervosa↗
PubMed1998

Pharmacological expression in rat hepatocytes of a gene transferred by an adenovirus vector enabled by a chimeric promoter containing multiple cyclic adenosine monophosphate response elements.

Using the adenovirus vector AdCF126(CRE8).Luc to deliver an expression cassette containing multiple cyclic adenosine monophosphate (cAMP) response elements driving the luciferase reporter gene, this study is directed toward evaluating the possibility of controlling genes transferred to the liver using pharmacological agents that raise hepatocyte cAMP levels. Infection of primary rat hepatocytes with AdCF126(CRE8).Luc yielded a low level of luciferase activity that was enhanced 16-fold by the addition of forskolin. Direct intrahepatic administration of the Ad vector in C57B1/6 mice resulted in low-level luciferase activity that was increased 76-fold by the administration of theophylline and 8-bromo-cAMP to increase cAMP levels. In contrast, animals receiving intrahepatic administration of a control vector containing a constitutively active Rous sarcoma virus (RSV) viral promoter driving the luciferase gene had no response to elevated cAMP Strikingly, delivery of the vector to the liver by the intravenous route permitted a 258-fold enhancement of liver luciferase activity following administration of the same cAMP-elevating agents. In comparison, a control Ad vector with the RSV promoter was not activated by the elevation in cAMP The maximum luciferase levels achieved by the combination of AdCF126(CRE8).Luc and pharmacological cAMP elevation was 45-fold greater than that with the RSV promoter. These results show the feasibility of using a chimeric promoter to permit pharmacological induction of high-level expression from an expression cassette transferred to the liver with an adenovirus vector, an approach that may be useful in a variety of liver-related gene-transfer strategies.

Adenoviridae↗
PubMed2003

Marine pharmacology in 2000: antitumor and cytotoxic compounds.

During 2000, marine antitumor pharmacology research aimed at the discovery of novel antitumor agents was published in 85 peer-reviewed articles. The purpose of this article is to present a structured review of the antitumor and cytotoxic properties of 143 marine natural products, many of them novel compounds that belong to diverse structural classes, including polyketides, terpenes, steroids and peptides. The organisms yielding these bioactive compounds comprised a taxonomically diverse group of marine invertebrate animals, algae, fungi and bacteria. Antitumor pharmacological studies were conducted with 19 marine natural products in a number of experimental and clinical models that defined or further characterized their mechanisms of action. Potentially promising in vitro cytotoxicity data generated with murine and human tumor cell lines were reported for 124 novel marine chemicals with as yet undetermined mechanisms of action. Noteworthy is the fact that marine anticancer research clearly remains a multinational effort, involving researchers from Austria, Australia, Brazil, Canada, England, France, Germany, Greece, Indonesia, Italy, Japan, New Zealand, Russia, Spain, South Korea, Switzerland, Taiwan, the Netherlands and the United States. Finally, this 2000 overview of the marine pharmacology literature highlights the fact that the discovery of novel marine antitumor agents continued at the same high level of research activity as during 1998 and 1999.

Animals↗
PubMed1992

Pharmacologic interactions between the resistance-modifying cyclosporine SDZ PSC 833 and etoposide (VP 16-213) enhance in vivo cytostatic activity and toxicity.

Cyclosporin A reverses multidrug resistance (MDR) and increases the in vivo cytostatic activity and toxicity of the anticancer agent etoposide (VP 16-213). SDZ PSC 833 (PSC 833), a non-immunosuppressive, non-toxic cyclosporin and very active modifier of P-gp 170-mediated MDR, elicits similar effects when administered with adriamycin. The underlying mechanisms, however, are not yet understood. The present pharmacological interaction study with PSC 833 and VP 16-213 was carried out to reveal the nature of this enhancement of cytostatic activity and toxicity. Rats pre-treated with either PSC-833 or solvent received a single dose of VP 16-213. Plasma levels of VP 16-213 were measured by high-performance liquid chromatography (HPLC). The resulting increase in cytostatic activity and toxicity of VP 16-213 mediated by PSC 833 was paralleled by marked changes in the pharmacokinetic parameters of VP 16-213 in vivo. Bioavailability and blood levels of VP 16-213 were significantly increased 30 min after administration if PSC 833 had been given before. The disappearance rate of VP 16-213 from the intravascular compartment was considerably slowed down by PSC 833. In drug-sensitive xenografts of human colon carcinoma, the PSC-833-induced pharmacologic changes in vivo could be counteracted by dose reduction of VP 16-213 while a full therapeutic potential was maintained. Doses of VP 16-213, 1.5 to 2 times smaller, combined with PSC 833, were as effective in terms of tumor-growth inhibition as the maximum tolerated dose of VP 16-213 alone. Thus, pharmacologic interactions between PSC 833 or other resistance modifiers and VP 16-213 and other cytostatic agents require careful attention if they are to be used in humans to overcome MDR.

Adenocarcinoma↗
PubMed1976

Limitations in interpretation of digoxin adsorption using averaged pharmacological response intensities.

In this paper, the interpretation of averaged pharmacological effect data for the cardiac glycoside digoxin is reconsidered through a comparison with theoretically simulated data. Four parameters, with their standard deviations calculated from the best-fit biexponential equation for the experimentally derived transformed pharmacological response intensity, were the basis for the random development of a series of 17 individual sets of data with average parameters and standard deviations identical to the values found experimentally. Parameters from these 17 data sets were averaged and randomly altered as a function of the standard deviations for each average. Loo-Riegelman analyses, modified for application to the peripheral compartment, and fraction remaining to be absorbed plots were made. Results of this comparison of experimental pharmacological simulated data indicate that the presence or absence of enterohepatic recycling may not be unambiguously determined here.

Adsorption↗
PubMed2003

Pharmacological inhibition of FGF receptor signaling inhibits LNCaP prostate tumor growth, promatrilysin, and PSA expression.

Previously we have shown that the matrix metalloproteinase matrilysin (MMP-7) is overexpressed in human prostate cancers compared with normal epithelium. However, the mechanism for this overexpression is not understood. Human prostate fibroblasts have been shown to express certain fibroblast growth factors (FGFs), including FGF-1. Evidence from our laboratory and others has indicated that FGFs can regulate the expression of certain matrix metalloproteinases, including matrilysin. The goal of this study was to determine whether pharmacological inhibition of FGFR signaling would alter LNCaP tumor growth as well as expression of promatrilysin when LNCaP cells were co-injected subcutaneously with human prostate fibroblasts into athymic nude mice. For these inhibitor studies, AG1-X2 beads were coated with the pharmacological FGFR inhibitor SU5402 and were co-injected along with LNCaP and human prostate fibroblast cells (PF). Mice injected with LNCaP/PF and LNCaP/PF/beads alone demonstrated significant tumor growth, whereas mice injected with LNCaP/PF/SU5402-coated beads showed a significant decrease in tumor volume and weight. Immunohistochemical analysis showed that significant promatrilysin expression in tumors was inhibited by the FGFR inhibitor SU5402. Serum prostate-specific antigen (PSA) and promatrilysin levels were measured by enzyme-linked immunosorbent assay. The mice injected with LNCaP/PF and LNCaP/PF/beads expressed promatrilysin and serum PSA levels that were inhibited by co-injecting with SU5402. Therefore, pharmacological inhibition of FGF receptor signaling results in a decrease in the growth of LNCaP tumors generated subcutaneously by co-injecting LNCaP cells and human prostate fibroblasts. The inhibition in tumor growth was correlated with a decrease in tumor promatrilysin expression and a decrease in serum promatrilysin and PSA.

Animals↗