Guidance on the management of adverse reactions induced by poly(ADP-ribose) polymerase inhibitors / 浙江大学学报·医学版

The common adverse reactions caused by poly (ADP-ribose) polymerase (PARP) inhibitors include hematological toxicity, gastrointestinal toxicity and fatigue. The main prevention and treatment of hematological toxicity include: regular blood tests, referral to hematology department when routine treatment is ineffective, and being alert of myelodysplastic syndrome/acute myeloid leukemia. The key points to deal with gastrointestinal toxicity include: taking medicine at the right time, light diet, appropriate amount of drinking water, timely symptomatic treatment, prevention of expected nausea and vomiting, and so on. For fatigue, full assessment should be completed before treatment because the causes of fatigue are various; the management includes massage therapy, psychosocial interventions and drugs such as methylphenidate and Panax quinquefolius according to the severity. In addition, niraparib and fluzoparib can cause hypertension, hypertensive crisis and palpitation. Blood pressure and heart rate monitoring, timely symptomatic treatment, and multidisciplinary consultation should be taken if necessary. When cough and dyspnea occur, high resolution CT and bronchoscopy should be performed to exclude pneumonia. If necessary, PARP inhibitors should be stopped, and glucocorticoid and antimicrobial therapy should be given. Finally, more attention should be paid to drug interaction management, patient self-management and regular monitoring to minimize the risk and harm of adverse reactions of PARP inhibitors.

Effects and Mechanism of PARP Inhibitor Olaparib on the Expression of NKG2D Ligands in HL-60 Cells / 中国实验血液学杂志

OBJECTIVE@#To investigate the regulatory effects of Olaparib on natural killer cell activating receptor (NKG2D) ligands expression on human acute myeloid leukemia (AML) cell line HL-60, and to explore the molecular mechanism of Olaparib on HL-60 cells.@*METHODS@#After HL-60 cells in logarithmic growth phase were treated with Olaparib at different concentrations for different times (24, 48 h), the expression of NKG2D ligand on the surface of HL-60 cells was detected by flow cytometry. Western blot was used to dectect the expression of ERK expression in HL-60 cells. The killing effect of NK cells to HL-60 cells was detected by CFSE/PI method.@*RESULTS@#10 μmol/L Olaparib could upregulate the expression of NKG2D ligand on the surface of HL-60 cell at 24 and 48 hours, while 5 μmol/L Olaparib could induce up-regulation of the expression of ULBP-2 and ULBP-3 at 48 hours. Western blot analysis showed that ERK phosphorylation of HL-60 cells was enhanced after treating with Olaparib. The killing effect of NK cells to HL-60 cells could be enhanced by Olaparib, however, ERK inhibitor could suppress the killing effect of NK cells to HL-60 cells.@*CONCLUSION@#Olaparib can upregulate NKG2D ligands expression on the surface of HL-60 cells and enhance the cytotoxicity of NK cell to HL-60 cells. The mechanism may be related to Olaparib promoting ERK phosphorylation expression.

Clinical pilot study on the rhinitis due to laryngopharyngeal reflux / 临床耳鼻咽喉头颈外科杂志

OBJECTIVE@#To explore the relevance between nasal symptoms and laryngopharyngeal reflux disease in patients with allergic rhinitis.@*METHOD@#Thirty patients of laryngopharyngeal reflux disease were diagnosed in ENT outpatient department in our hospital. All patients have symptoms of sneeze, nasal discharge as chief complaint and they responded no effect for other normal treatment for nasal-sinusitis at least three months. Orally before meals, a dose of 5 mg Mosapride citrate each time, three times a day for 7 days. Orally before meals, a dose of 20 mg Esomeprazole each time, two times a. day for 2-3 months. Nasal spray, one spray of azelastine hydrochloride once, two times a day for 2 month.@*RESULT@#Laryngopharyngeal reflux symptom scores at four time points (the first visit, post treatment 15 days, 45 days, 75 days) were analyzed by repeated measures analysis of variance. There is a significant difference in four time points.@*CONCLUSION@#Laryngopharyngeal reflux disease has a strong association with allergic rhinitis. Patients who has allergic rhinitis nasal symptoms as chief complaint must be exclude, the laryngopharyngeal reflux disease first.

Neuropsychomotor developmental delay: conceptual map, term definitions, uses and limitations / Atraso do desenvolvimento neuropsicomotor: mapa conceitual, definições, usos e limitações do termo

OBJECTIVE: To retrieve the origin of the term neuropsychomotor developmental delay" (NPMD), its conceptual evolution over time, and to build a conceptual map based on literature review. DATA SOURCE: A literature search was performed in the SciELO Brazil, Web of Science, Science Direct, OneFile (GALE), Pubmed (Medline), Whiley Online, and Springer databases, from January of 1940 to January of 2013, using the following keywords: NPMD delay, NPMD retardation, developmental delay, and global developmental delay. A total of 71 articles were selected, which were used to build the conceptual map of the term. DATA SYNTHESIS: Of the 71 references, 55 were international and 16 national. The terms developmental delay and global developmental delay were the most frequently used in the international literature and, in Brazil, delayed NPMD was the most often used. The term developmental delay emerged in the mid 1940s, gaining momentum in the 1990s. In Brazil, the term delayed NPMD started to be used in the 1980s, and has been frequently cited and published in the literature. Delayed development was a characteristic of 13 morbidities described in 23 references. Regarding the type of use, 19 references were found, with seven forms of use. Among the references, 34 had definitions of the term, and 16 different concepts were identified. CONCLUSIONS: Developmental delay is addressed in the international and national literature under different names, various applications, and heterogeneous concepts. Internationally, ways to improve communication between professionals have been indicated, with standardized definition of the term and use in very specific situations up to the fifth year of life, which was not found in Brazilian publications. .

OBJETIVO: Resgatar a origem do termo atraso do desenvolvimento neuropsicomotor (DNPM), sua evolução conceitual ao longo do tempo e construir mapa conceitual do termo com base em busca bibliográfica. FONTES DE DADOS: Foi realizada busca nas bases de dados eletrônicas do Portal da Capes, que incluem Scielo Brazil, Web of Science, Science Direct, OneFile (GALE), Pubmed (Medline), Whiley Online e Springer, referente a Janeiro/1940-Janeiro/2013. Palavras-chave: atraso e retardo do DNPM, developmental delay e global developmental delay. Foram selecionados 71 artigos e construído o mapa conceitual do termo. SÍNTESE DE DADOS: Das 71 referências, 55 eram internacionais e 16 nacionais. Os termos mais encontrados foram global developmental delay e developmental delay na literatura internacional e retardo e atraso do DNPM no Brasil. Internacionalmente, o termo surgiu em meados da década de 40 ganhando força nos anos 90. No Brasil, o termo começou a ser usado na década de 80 e vem sendo frequentemente citado na literatura. O atraso é citado em 23 trabalhos como característica presente em 13 tipos de condições clínicas. Com relação ao uso, foram encontrados 19 estudos, com sete situações de uso. Dentre os artigos revisados, 34 deles apresentaram definições, sendo identificados 16 conceitos diferentes. CONCLUSÕES: O atraso do desenvolvimento é abordado na literatura internacional e nacional sob diversos nomes, diferentes aplicações e conceitos heterogêneos. Internacionalmente, apontam-se caminhos para melhorar a comunicação entre profissionais, com definição padronizada do termo e uso em situações específicas até o quinto ano de vida, o que não foi encontrado nas publicações nacionais. .

Clinical study of the combination therapy with intranasal antihistamine and nasal corticosteroids in the treatment of nasal obstruction of persistent non-allergic rhinitis / 临床耳鼻咽喉头颈外科杂志

OBJECTIVE@#To determine if greater efficacy could be achieved with the intranasal antihistamine azelastine and the intranasal corticosteroid fluticasone propionate used concurrently in the treatment of nasal obstruction of persistent non-allergic rhinitis.@*METHOD@#A total of 162 persistent non-allergic rhinitis cases with moderate to severe nasal obstruction were randomized to treatment with the following: the combination therapy or nasal corticosteroids monotherapy. Efficacy was assessed by change from baseline in nasal obstruction score at week 2 and week 6 visits. The perceptions of global treatment satisfaction(convenience, side effects, cost and effectiveness) in both groups were analyzed.@*RESULT@#In both groups, the nasal obstruction score assessment descended significantly at week 2 and week 6 visits versus at baseline (all P < 0.01). At week 2 and week 6 visits, the nasal obstruction score in the combination therapy groups were significantly improved than that in nasal corticosteroids monotherapy groups (all P < 0.01). The perceptions of global treatment satisfaction in the combination therapy groups were significantly better (P < 0.05).@*CONCLUSION@#Azelastine nasal spray and intranasal corticosteroid in combination may provide a substantial therapeutic benefit for patients with persistent non-allergic rhinitis, especially nasal obstruction. The combination therapy was well tolerated and safety.

Research progresses of the PARP inhibitors for the treatment of cancer / 药学学报

The poly(ADP-ribose) polymerases (PARPs) is an important group of enzymes in DNA repair pathways, especially the base excision repair (BER) for DNA single-strand breaks (SSBs) repair. Inhibition of PARP in DNA repair-defective tumors (like those with BRAC1/2 mutations) can lead to cell death and genomic instability, what is so called "synthetic lethality". Currently, PARP inhibitors combined with cytotoxic chemotherapeutic agents in the treatment of BRCA-1/2 deficient cancers are in the clinical development. In this review, we will be focused on the development of combination application of PARP inhibitors with other anticancer agents in clinical trials.

Synthesis and immunosuppressive effects of novel phthalazine ketone derivatives / 药学学报

A series of phthalazine ketone compounds were synthesized and the structures were confirmed by H NMR and HR-MS spectrum. All target compounds were obtained through 7 steps, including selective reduction, nitration, bromination, ring enlargement, reduction, Knoevenagel and acylated reaction. The compounds were evaluated for their immunosuppressive effects of T-cell proliferation and inhibitory activity of IMPDH type II in vitro, as well as their structure-activity relationship were assessed. Several compounds exhibited strong immunosuppressive properties, especially compounds 7f and 7h, with IC50 values of 0.093 micromol x L(-1) and 0.14 micromol x L(-1) respectively, which were superior to mycophenolic acid. The information obtained from the studies may be useful for further research on the immunosuppressive agents.

PARP inhibitors: its role in treatment of cancer / 癌症

PARP is an important protein in DNA repair pathways especially the base excision repair (BER). BER is involved in DNA repair of single strand breaks (SSBs). If BER is impaired, inhibiting poly(ADP-ribose) polymerase (PARP), SSBs accumulate and become double stand breaks (DSBs). The cells with increasing number of DSBs become more dependent on other repair pathways, mainly the homologous recombination (HR) and the nonhomologous end joining. Patients with defective HR, like BRCA-deficient cell lines, are even more susceptible to impairment of the BER pathway. Inhibitors of PARP preferentially kill cancer cells in BRCA-mutation cancer cell lines over normal cells. Also, PARP inhibitors increase cytotoxicity by inhibiting repair in the presence of chemotherapies that induces SSBs. These two principles have been tested clinically. Over the last few years, excitement over this class of agents has escalated due to reported activity as single agent in BRCA1- or BRCA2-associated ovarian or breast cancers, and in combination with chemotherapy in triple negative breast cancer. This review covers the current results of clinical trials testing those two principles. It also evaluates future directions for the field of PARP inhibitor development.

The evolution of phase I trials in cancer medicine: a critical review of the last decade / 癌症

The advent of targeted therapies, combined with an unsustainable rate of failure in oncology drug development, has resulted in a number of new approaches to clinical trials. Early clinical trials are no exception, with efforts to improve the eventual success rate of late stage trials through evolving phase I trial methodologies, the addition of extensive pharmacodynamic studies, and early adoption of patient selection strategies. Unfortunately, some of these new approaches have met with mixed results. Furthermore, no clear metrics are available to determine whether these designs are more successful than previous strategies. This review examines the evolution of phase I trials and draws upon several examples of strategies that have been successful as well as those that have not, and outlines a pragmatic approach to phase I trials as our understanding of the molecular biology of individual malignancies emerges.

Azelastine versus beclomethasone in the treatment of perennial allergic rhinitis

To compare the efficacy of topical nasal application of Azelastine HCL with Beclomethasone in treating perennial allergic rhinitis. It was a quasi-experimental interventional study conducted on 60 patients of Allergic Rhinitis, presenting to ENT Department Combined Military hospital Rawalpindi from 1[st] January 2008 to 30 June 2008. Patients fulfilling the criteria were divided into two groups of 30 patients each. Group I was given Azelastine nasal spray, while group II was given Beclomethasone nasal spray for topical application. Out of sixty patients 37 were males and 23 were females. Mean age for group I was 28.97 years with Standard Deviation of 6.13. In group II, mean age was 28.3 years with Standard Deviation of 5.62. The symptoms of Perennial Allergic Rhinitis were better controlled in patients treated with topical application of Beclomethasone as compare to Azelastine. Beclomethasone is more effective than Azelastine for the control of the symptoms of Perennial Allergic Rhinitis

Effects of PTK787 on cell proliferation and expression of fak mRNA in K562 / 中国实验血液学杂志

The aim of this study was to investigate the effects of tyrosine kinase inhibitor PTK787 on cell proliferation, cell cycle and the expression of fak mRNA of human chronic myeloid leukemia (CML) cell line K562, and to explore the mechanism of PTK787 against acute myeloid leukemia. The MTT method was used to detect the effects of PTK787 in various concentrations and at different time points on proliferation of K562 cells; the flow cytometry was used to determine the effects of PTK787 in different concentrations on cell cycle of K562 cells; the RT-PCR was used to assay the expression of fak mRNA in K562 cells treated with PTK787 for 48 hours. The results showed that along with increasing of the concentration and prolonging of time, the inhibitory rate of PTK787 on K562 proliferation was gradually enhanced. The comparison between various concentration groups at same time or comparison between various time groups in same concentration showed significant differences (p < 0.05), in which the effect of 320 micromol/L PTK787 on cells was strongest, while the continuous increase of PTK787 concentration or prolong of action time did not enhance the inhibitory rate on K562 proliferation. With increasing of drug concentration, the cell proportion in G(1) phase gradually increased, the cell proportion in S phase gradually decreased, the comparison between various groups revealed significant differences (p < 0.05), however the continuous increase of drug concentration from 160 micromol/L did not obviously change the cell proportion in phases of cell cycle. With increasing of drug concentration, the expression of fak mRNA in K562 cells gradually reduced with significant differences between various groups (p < 0.05), but with continuous increase of drug concentration from 160 micromol/L, the effect of PTK787 on the expression of fak mRNA in K562 cells also did not obviously change. It is concluded that the PTK787 shows effect of anti-leukemia cells through inhibiting transformation of the K562 cells from G(1) phase into S phase and decreasing the expression of fak mRNA in cells.

Effect of PKC signalling pathway and aldose reductase on expression of fibronectin induced by transforming growth factor-β1 in human mesangial cells / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the effect of PKC signalling pathway and aldose reductase (AR) on the expression of fibronectin (FN) induced by transforming growth factor-β1 (TGF-β1).</p><p><b>METHODS</b>Human mesangial cells (HMCs) were cultured and transfected with pcDNA3-AR, and subject to AR gene silencing with small interfering RNA (siRNA) and then the cell was treated with recombinant human TGF-β1. The AR mRNA expression in the HMCs was examined using real time RT-PCR and protein expression of AR and FN was detected by Western blotting.</p><p><b>RESULTS</b>The cultured HMC treated with TGF-β1 showed increased expression of AR and FN, the normal HMC showed not reduced expression of FN after incubation with single inhibitors of AR.Pre-incubation of cells with inhibitors of AR and PKC, then the different groups of cells were treated with TGF-β1, and the induction effect on FN expression was suppressed (34%) in HMC. HMCs transfected with AR showed a strong protein expression of FN, which was increased by 3.6-fold after treatment with TGF-β1 (P < 0.05), and the induction effect on FN expression was suppressed by GÖ6983 (42%) in HMCs (P < 0.05). The HMC with AR gene knock-down by siRNA showed a decreased expression of AR and 90% decrease of FN protein in HMCs (P < 0.01), and TGF-β1-induced up-regulation of FN was significantly suppressed by siRNA (12%) in HMCs (P < 0.01).</p><p><b>CONCLUSIONS</b>AR is capable of regulating FN expression only in the presence of TGF-β1, and this reaction is possibly accomplished through the activation of PKC signalling pathway.</p>

[Serious lead poisoning in oral and inhaled opium abuser]

A 25 year old man who referred with abdominal pain, nausea and progressive vomiting since 2 months ago and 7kg weight loss from this time. Also he was complaining from generalized bone pain especially back pain and jaundice. The patient has a long time history of addiction with oral and inhalation form of narcotics. In physical exam pallorness and icter of mucosa was observed. In mouth examination bluish pigmentation seen at the gum-tooth line. Hepatosplenomegaly and lymphadenopathy was not detected. Upper GI endoscopy was normal. And in lab tests hepatic aminotransferases were increased but alkalin phosphatase was in normal range also indirect billirubin was increased too. CBC test non auto immune hemolytic anemia was deteded, and direct and indirect combs test was negative. BMB and BMA evaluation hyperplasia of erythroid was shown. The patient had a history of smoking and oral narcotics use from 6 years ago. According to all symptoms with clinical doubt of lead poisoning the very high level of lead in narcotic sample was reported and in blood analysis very high level of lead [350mg/dl] was detected. The patient was treated with Ca.EDTA and BAL with decreasing lead level and the symptoms were recovered. There are some reports Similar this case [due to oral narcotics contain Lead] in Iran

Comparative efficacy of steroid nasal spray versus antihistamine nasal spray in allergic rhinitis.

This prospective randomized case controlled study was conducted to determine the efficacy of antihistamine (azelastine) nasal spray and compare it to steroid (beclomethasone) nasal spray on the symptoms of allergic rhinitis. Seventy five symptomatic patients of allergic rhinitis were included in this study. Diagnosis was made on the basis of history and physical examination. The patients were divided into three groups randomly. Group A was treated with Azelastine nasal spray, Group B was treated with Beclomethasone nasal spray and Group C was control group and only treated with steam inhalation. Efficacy of the treatment was assessed in the terms of Total Rhinitis Symptom Complex (TSC) scores and individual symptom score which was calculated on the basis of Okuda's grading system. Base line total symptom complex (TSC) scores were reduced in group A and group B by 84.0% after 4 week treatment whereas in group C it was reduced by only 38.0%. Decrease in mean score for sneezing was 95.0% in group A and group B whereas it was only 28.3% in group C. Similarly decrease in mean score for rhinorrhoea in azelastine group was 94.4% and in beclomethasone group was 95.3% in comparison to steam inhalation group where it was 25.0%. Only the beclomethasone reduced nasal stuffiness score significantly by 95.0%. No significant adverse effects of the drugs were observed. The present study establishes the relative efficacy and tolerability ofazelastine nasal spray as compared to beclomethasone nasal spray in symptomatic patients of allergic rhinitis.

Evaluation of apoptosis-induction by newly synthesized phthalazine derivatives in breast cancer cell lines.

Newly synthesized phthalazine derivatives including copper and platinum complexes were evaluated for cytotoxicity in human breast cancer cell lines. The cells were incubated with the compounds (100 microM) for 72 h and cytotoxicity, apoptosis and DNA content were measured by flow cytometery. Our results suggest that the parent (H1-2), copper (C1-2)- and platinum (P1-2)-derivatized compounds were relatively more active in inducing apoptosis and cell killing in both human breast cancer cell lines, MDA-MB-231 cells being the more sensitive. Other compounds showed weak or no response towards these parameters except H-5 causing 40% apoptosis in MDA-MB-231 cells. Addition of copper or platinum in the structures generally reduced the apoptotic potential. Possible roles for structure activity relationships are discussed.

Effect of glycine site/NMDA receptor antagonist MRZ2/576 on the conditioned place preference and locomotor activity induced by morphine in mice / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

<p><b>OBJECTIVE</b>To study the effect of glycine site/NMDA (N-methyl-D-aspartate) receptor antagonist MRZ2/576 on the conditioned place preference (CPP) and locomotor activity induced by morphine in mice.</p><p><b>METHODS</b>Different doses (1.25, 2.5 and 5 mg/kg, i.p.) of MRZ2/576 were used to evaluate the effect of MRZ2/576 on the acquisition and expression of CPP induced by morphine (5 mg/kg) in mice. In addition, we examined the locomotor activity of mice in conditioning and testing phase of CPP paradigm.</p><p><b>RESULTS</b>MRZ2/576 alone could not establish place preference, but a 5 mg/kg dose of MRZ2/576 could block both acquisition and expression of morphine-induced CPP. In testing phase of CPP, there was no statistical difference for locomotor activity between the groups; injection of MRZ2/576 showed a dose-dependent decrease of locomotor activity on both control and morphine-treated mice, especially 5 mg/kg of MRZ2/576 significantly suppressed the locomotor activity of mice.</p><p><b>CONCLUSION</b>Based on the present results, we assume that MRZ2/576 can antagonize the rewarding effect of morphine, suggesting that this glycine site/NMDA receptor antagonist could be used to treat addictions due to its light side effect profile.</p>

Utility of 4-[2-[2-[4-methoxyphenyl] vinyl]-4-oxo-4H-quinazolin-3-yl] benzoic acid hydrazide

Quinazoline derivatives were reported to have different biological activities, including analgesic, antipyretic, antimicrobial, fungicidal, antidepressant and other central nervous system affecting activities[1-7]. The use of quinazoline derivative as starting material for the design and synthesis of new heterocyclic compounds with the aim of preparing potent biologically active compounds is a subject of recent interest[8, 9]Now, we report a facile synthesis of several heterocyclic compounds containig pyrazole, oxadiazine, phthalazine and triazine to test them against different microorganisms

Effects of aldose reductase on the expression of fibronectin and collagen IV in cultured rat renal mesangial cells / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the effect of aldose reductase (AR) on expression of fibronectin and collagen IV in cultured rat renal mesangial cells (MsC).</p><p><b>METHODS</b>AR expression plasmid vector (pCDNA3-AR) was constructed by restriction endonuclease digestion and ligation procedures. Stable expression of AR in MsC was established by Lipofectin transfection. Western blot and immunofluorescence analyses were performed to verify the transfection efficiency. Expression of fibronectin and collagen IV proteins were analyzed using Western blot.</p><p><b>RESULTS</b>Expression of fibronectin and collagen IV in naive MsC treated with TGF-beta1 was upregulated in comparison to that of the untreated naive MsC (P < 0.01). MsC transfected with pCDNA3-AR showed a remarkable increase of expression of fibronectin and collagen IV (P < 0.01). Aldose reductase inhibitors (Sorbinil and Zopolrestat) significantly inhibited the expression of fibronectin and collagen IV in naive MsC (P < 0.05).</p><p><b>CONCLUSIONS</b>Overexpression or inhibition of AR activity significantly alters the expression of fibronectin and collagen IV proteins in cultured rat MsC, suggesting that AR plays a significant role in the pathogenesis of glomerulosclersis.</p>

Effects of aldose reductase transfection on the proliferation of rat mesangial cells in vitro / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the effects of aldose reductase (AR) on the proliferation of rat mesangial cells (MsC) in vitro and to investigate its mechanism.</p><p><b>METHODS</b>Cell proliferation was assessed by MTT colorimetric assay. Cell cycle and apoptosis were analyzed by flow cytometry. The growth of normal MsC and AR transfected MsC was compared. The proliferation of PDGF-BB and cellular growth stimulation by 10% NBS were investigated using AR inhibitors (ARI) Sorbinil and Zopolrestat. The effects of PDGF-BB on the expression of AR, p65 and c-Jun were assessed by Western blot. Activation of AP-1 was measured by EMSA.</p><p><b>RESULTS</b>AR expression of transfected MsC was distinctly higher than that of the control. Transfected MsC grew quicker than normal cells. ARI partially inhibited the proliferation of transfected MsC under the stimulation of PDGF-BB and 10% NBS, whereas 10% NBS had no effect on normal MsC. PDGF-BB upregulated the expression of AR and c-Jun, but had no effect on p65. The upregulation of c-Jun and the activation of AP-1 could be attenuated by ARI.</p><p><b>CONCLUSION</b>AR may participate in the pathological proliferation of MsC through the pathway related to the activation of AP-1.</p>

Inhibition of vascular endothelial growth factor (VEGF) as a novel approach for cancer therapy

Of the numerous growth factors and cytokines that have been shown to have angiogenic effects, vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), appears to be a key factor in pathological situations which involve neovascularization as well as enhanced vascular permeability. Our aim was to design a low molecular weight synthetic molecule that potently and selectively blocks the VEGF/VEGF receptor system after oral administration, suitable for the chronic therapy of VEGF-dependent pathological neovascularization. PTK787/ZK 222584 is a potent inhibitor of VEGF receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, like the PDGFR-beta tyrosine kinase, c-Kit and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families such as EGFR, FGFR-1, c-Met and Tie-2 or intracellular kinases like c-Src, c-Abl, PKC-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of KDR, and endothelial cell proliferation, migration and survival in the nanomolar range in cell based assays. In concentrations up to 1 microM, PTK787/ZK 222584 does not have any cytotoxic or anti-proliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF- and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once daily oral dosing (25-100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown subcutaneously in nude mice, as well as a murine renal carcinoma and its metastases in syngeneic, orthotopic models. Histological examination of tumors reveals inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 also significantly inhibits ascites formation induced by a human ovarian carcinoma grown in the peritoneum of nude mice as well as pleural effusion induced by a human lung adenocarcinoma in nude mice. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent, or impair hematopoetic recovery following concomitant cytotoxic anti-cancer agent challenge. These studies indicate that compounds that inhibit the effects of VEGF, such as PTK787/ZK 222584, have the potential to provide a novel, effective and well-tolerated therapy for the treatment of solid tumors. These agents may also provide a new therapeutic approach for the treatment of other diseases where angiogenesis plays an important role.