Basic Fibroblast Growth Factor Levels Research Articles

Phase II study of thalidomide in patients with metastatic malignant melanoma

Thalidomide has anti-angiogenic and immunomodulatory activity, exhibiting antitumour effects in patients with multiple myeloma and, more rarely, in several other solid tumours. We evaluated the single-agent antitumour activity and toxicity profile of thalidomide in patients with metastatic malignant melanoma, as well as its plasma pharmacokinetics and pharmacodynamic effects [vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF) levels]. A two-stage Gehan method was used with a stopping rule after 14 consecutive non-responding patients. Thalidomide was given orally at a daily dose of 200 mg/day, which was then escalated every 2 weeks by 200 mg/day as tolerated to a maximum of 800 mg/day. Patients were evaluated every 8 weeks for response using the World Health Organization (WHO)-27 criteria. Fourteen patients were enrolled and no objective responses were observed, with one stable disease and one mixed response. The dose-limiting toxicities were constipation, dizziness and somnolence. Other toxicities were oedema, neuropathy, dry skin, dry mouth, tremor and fatigue. The plasma pharmacokinetics of thalidomide were comparable with those of previous studies in normal volunteers and in patients with advanced prostate cancer. Serum levels of b-FGF and VEGF did not change significantly following drug administration. In conclusion, thalidomide showed poor activity, but acceptable toxicity, in patients with metastatic melanoma. Future studies should explore this agent in combination with other biological agents or cytotoxic agents, such as temozolomide.

Angiogenic Cytokines: Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor Levels in Serum of Children with Hematopoietic Malignancies and Solid Tumors.

Angiogenesis is a process of blood vessel formation from the preexisting capillaries. It plays an essential role of growth and development of cancer. The most important angiogenic stimulators are Vascular Endothelial Growth Factor (VEGF) and basic Fibroblast Growth Factor (bFGF). The aim of the study was to evaluate the serum levels of VEGF and bFGF in children with solid tumors, hematological malignancies and in healthy controls. Patients: 110 children (33 with solid tumors and 77 with hematological malignancies, including 46 with acute lymphoblastic leukemia and 17 with acute myeloblastic leukemia) (56 male and 54 female) aged 2–18 years (median 8.5 years) and 70 healthy controls (31 male and 39 female) aged 3–18 years (median 13 years). For the quantitative determination the Quantikine VEGF and bFGF immunoassay, a solid-phase enzyme-linked immunosorbent assay method was used. Elevated VEGF and bFGF were defined as being higher than the 95 percentile value in control group. Results: At the time of diagnosis the range of VEGF serum levels in all cancer patiens was 0–2691.3 pg/ml, and in remission 6.08–967.67 pg/ml; while the range of bFGF at diagnosis was 0–64.48 pg/ml, and in remission 0–32.52 pg/ml. In all children with cancer, serum levels of VEGF and bFGF were significantly more often elevated than in healthy controls (p<0.004; p<0.0005). At diagnosis, almost 12% patients had simultaneously elevated serum levels of VEGF and bFGF. Among patients with solid tumors at the time of diagnosis, elevated levels of VEGF and bFGF was observed in 42% and 60%, respectively. There were no differences between serum levels of these factors in patients in remission and in control group. In patients with progression, serum levels of VEGF and bFGF were higher, when compared to levels of these factors at diagnosis. The range of serum levels of VEGF in children with solid tumors at the time of diagnosis was 85.96–2691.3 pg/ml (median 365.48 pg/ml), and in remission 6.08–787.16 pg/ml (median 204.1 pg/ml). The median level of VEGF at diagnosis in children with hematopoietic malignancies (range 0–1869.6 pg/ml, median 111.6 pg/ml) was lower than in children with solid tumors (p<0.0005). In children with acute leukemias at diagnosis, serum levels of VEGF were significantly lower than in children with lymphomas (p<0.0003) and in controls (p<0.05). These results suggest that evaluation of serum levels of VEGF and bFGF can be helpful for monitoring activity of cancer, particularly in solid tumors and in the future can be a target of anti-angiogenic therapy.

Elevated Basic Fibroblast Growth Factor Levels in Patients With Pulmonary Arterial Hypertension

Cellular growth in the vascular wall, including endothelial and smooth-muscle cell proliferation, is recognized as a component of the obstructive vasculopathy observed in the small vessels of the lungs in pulmonary arterial hypertension (PAH). We hypothesized that angiogenic growth factors may have a role in the molecular mechanisms underlying this cellular proliferation. Case-control study. Multicenter, tertiary care hospitals. We studied 117 patients with PAH and 60 control subjects. We measured levels of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in the blood and urine of these subjects using an enzyme-linked immunoassay. Median levels of urinary and plasma bFGF were significantly higher in patients with PAH compared to normal control subjects. There was a difference in levels of urine and plasma bFGF according to etiology of pulmonary hypertension, with the highest levels seen in patients with primary pulmonary hypertension. Levels of urine or plasma VEGF were not significantly different between patients and control subjects. Patients with PAH have substantial alterations in urine and plasma levels of bFGF. This molecule may have a role as a mitogenic factor in the endothelial and smooth-muscle cell proliferation seen in PAH.

Effect of intravenous heparin on serum levels of endostatin, VEGF and HGF: author's reply.

We thank Dr Bhatia, Dr Clesham and Dr Turner for their interest in our paper [1], and we agree with them that the studies on the serum levels of endostatin, VEGF and HGF under administration of heparin should be interpreted very carefully, and there is an important limitation in our study. However, we disagree with them on some points as follows. We think that the significant decrease in serum VEGF levels after reperfusion may be due to down-regulation of VEGF production (although we did not state in our paper) as well as internalization of VEGF after binding to its receptor (which may be facilitated by heparin [2]). VEGF was shown to be internalized in HUVECs (human umbilical vein endothelial cells) [3]. In fact, we found that VEGF concentrations in culture supernatants of cardiac myocytes increased rapidly and then decreased in response to acute hypoxia in vitro without addition of any drugs including heparin (Y. Seko, unpublished work). This is also the case for endostatin. Recently, it has been reported that AIDS-related Kaposi's sarcoma cells rapidly internalize endostatin [4]. We also found that concentrations of endostatin in culture supernatants of cardiac myocytes subjected to hypoxia in vitro increased a little later than those of VEGF, suggesting that VEGF and endostatin are similarly released into culture supernatants in response to hypoxia (Y. Seko, unpublished work).Kawamoto et al. [5] reported that the serum concentration of VEGF in patients with acute myocardial infarction was reduced by up to 93% 1 h after administration of intravenous heparin. However, it is strange that the authors [5] did not report the serum VEGF levels at the time of admission before the start of heparin administration, and that heparin administration markedly decreased the serum VEGF level, but had no effects on the serum bFGF (basic fibroblast growth factor) level, although both growth factors are heparin-binding proteins. Moreover, we analysed the same serum samples with an ELISA kit from R&D Systems and that from Immuno-Biological Laboratories (as used by Kawamoto et al. [5]), but the data were quite different between the two kits. As we stated in our paper [1], marked elevation of serum levels of HGF after reperfusion was thought to be at least in part (but not entirely) due to heparin administration. However, we could not exclude a possibility that HGF may be released into the circulation in response to reperfusion and play a protective role against the reperfusion-induced oxidative stress [6].In conclusion, to know the precise effects of myocardial ischaemia/reperfusion on the serum levels of endostatin, VEGF and HGF, further studies using animal models without administration of any drugs, including heparin, are needed.

Antitumor effects of thalidomide analogs in human prostate cancer xenografts implanted in immunodeficient mice.

Thalidomide has demonstrated clinical activity in various malignancies including androgen-independent prostate cancer. The development of novel thalidomide analogs with better activity/toxicity profiles is an ongoing research effort. Our laboratory previously reported the in vitro antiangiogenic activity of the N-substituted thalidomide analog CPS11 and the tetrafluorinated analogs CPS45 and CPS49. The current study evaluated the therapeutic potential of these analogs in the treatment of prostate cancer in vivo. Severely combined immunodeficient mice bearing s.c. human prostate cancer (PC3 or 22Rv1) xenografts were treated with the analogs at their maximum tolerated doses. Tumors were then excised and processed for ELISA and CD31 immunostaining to determine the levels of various angiogenic factors and microvessel density (MVD), respectively. CPS11, CPS45, and CPS49 induced prominent and modest growth inhibition in PC3 and 22Rv1 tumors, respectively. Thalidomide had no effect on tumor growth in either xenograft. Vascular endothelial growth factor and basic fibroblast growth factor levels were not significantly altered by any of the thalidomide analogs or thalidomide in both PC3 and 22Rv1 tumors. CPS45, CPS49, and thalidomide significantly reduced PC3 tumor platelet-derived growth factor (PDGF)-AA levels by 58-82% (P < 0.05). Interestingly, treatment with the analogs and thalidomide resulted in differential down-regulation (>/=1.5-fold) of genes encoding PDGF and PDGF receptor isoforms as determined by DNA microarray analysis. Intratumoral MVD of 22Rv1 xenografts was significantly decreased by CPS45 and CPS49. CPS49 also reduced MVD in PC3 xenografts. Thalidomide analogs CPS11 and 49 are promising anti-cancer agents. PDGF signaling pathway may be a potential target for these thalidomide analogs. Detailed microarray and functional analyses are under way with the aim of elucidating the molecular mechanism(s) of action of these thalidomide analogs.

Multiple vulnerability of photoreceptors to mesopic ambient light in the P23H transgenic rat

The P23H transgenic rat was engineered to mimic a human form of retinal degeneration caused by a mutation in rhodopsin. We have tested whether the P23H transgene influences the vulnerability of photoreceptors to modest variations in ambient light, well within the physiological range. P23H-3 (P23H line 3) and control Sprague–Dawley (SD) rats were raised in cyclic light (12 h light, 12 h dark), with the light phase set at either 5 lx (‘scotopic-reared’) or 40–60 lx (‘mesopic-reared’). Mesopic rearing reduced the length of outer segments (OSs) in both SD and P23H-3 strains, but the shortening was more marked in the P23H-3 strain. Mesopic rearing was associated with thinning of the ONL, again more prominently in the P23H-3. Correspondingly, mesopic rearing increased the rate of photoreceptor death (assessed by TUNEL labelling), the increase occurring during early postnatal life. Mesopic rearing upregulated FGF-2 (basic fibroblast growth factor) levels in photoreceptors and glial fibrillary acidic protein (GFAP) in Müller cells in both SD and P23H-3 strains; again the changes were more marked in the P23H-3. Finally, mesopic rearing decreased the amplitude of the a-wave of the ERG in both strains; again the effect was greater in the P23H-3 strain. The ERG decline induced in both strains by mesopic-rearing can be explained by a reduction of functional OS membrane, due to a combination of photoreceptor death and OS shortening. The P23H-3 transgene makes photoreceptors abnormally vulnerable to modest levels of ambient light, their vulnerability being evident in multiple ways. In humans suffering photoreceptor degeneration from comparable genetic causes, light restriction may preserve the number and the function of photoreceptors.

Serum syndecan-1, basic fibroblast growth factor and osteoprotegerin in myeloma patients at diagnosis and during the course of the disease.

Neovascularisation and bone resorption are related to myeloma disease activity. To investigate the possible prognostic importance of serum syndecan-1, basic fibroblast growth factor (bFGF) and osteoprotegerin (OPG) levels, the relationship between them, with parameters of disease activity and the effect of treatment on their levels. Twenty-seven patients were studied from diagnosis and an additional five from remission, for a median follow-up of 40 months. Twenty-three patients received chemotherapy plus bisphosphonates and nine only bisphosphonates. Sera from 11 healthy individuals (HI) were used as controls. Cytokines were determined by commercially available enzyme-linked immunosorbent assays (ELISA) kits. In HI, median syndecan-1 was 40 ng/mL (28-75), bFGF 8 pg/mL (7-30), OPG 35 pg/mL (4-100). Pretreatment median serum syndecan-1 was 177.5 ng/mL (34-3500), bFGF 11.5 pg/mL (8-65) and OPG 100 pg/mL (4-1000). Pretreatment syndecan-1, bFGF and OPG serum levels were increased in patients compared with HI (P = 0.001, 0.03 and 0.01, respectively). Syndecan-1 and bFGF levels were correlated with stage (P = 0.004 and 0.03, respectively). Both syndecan-1 and OPG levels were correlated with beta2M (P = 0.04 and 0.01, respectively). Patients with elevated syndecan-1 and bFGF serum levels had shorter survival than patients with normal levels (P = 0.01 and 0.05, respectively). After chemotherapy syndecan-1 and OPG levels were found to be decreased in responders and syndecan-1 level was reduced in patients receiving bisphosphonates alone. Pretreatment syndecan-1, bFGF and OPG levels were found to be increased at diagnosis. Syndecan-1 and OPG fluctuated according to MM activity. Elevated serum syndecan-1 and bFGF levels predicted short survival.

The Effect of Silicone Gel on Basic Fibroblast Growth Factor Levels in Fibroblast Cell Culture

Topical silicone gel has shown promise in the treatment of hypertrophic and keloid scars. However, its mechanism of action remains undetermined. To investigate whether the presence of silicone alters the secretion of basic fibroblast growth factor (bFGF), a key cytokine involved in the scar formation process. Serum-free fibroblast cell cultures were established from normal, keloid, and fetal skin, which heals without scarring, and exposed to silicone gel. Serial cell counts were performed, and supernatants were collected for bFGF quantification by enzyme-linked immunosorbent assay at 4, 24, 72, and 120 hours. Growth curves were similar and no statistically significant differences in population doubling times were observed between treated and untreated specimens. Statistically significant differences in bFGF levels between treated and untreated normal fibroblasts were observed at 24, 72, and 120 hours after cell culture initiation. Differences in bFGF levels between treated and untreated fetal fibroblasts that approached statistical significance were observed at 72 and 120 hours. These results suggest that silicone gel is responsible for increased bFGF levels in normal and fetal dermal fibroblasts. We postulate that silicone gel treats and prevents hypertrophic scar tissue, which contains histologically normal fibroblasts, by modulating expression of growth factors such as bFGF. Our data support the hypothesis that substances that favorably influence wound healing do so by correcting a deficiency or overabundance of the growth factors that orchestrate the tissue repair process.

Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) levels, as prognostic indicators in NSCLC.

Non-small cell lung cancer (NSCLC) tissue produces numerous growth factors, which are multifunctional and considered predictive of patient survival. This study sought to evaluate the relationship between concentrations of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) in NSCLC tissue and clinicopathological factors, and determine whether these factors correlate with long-term survival. We retrospectively investigated 71 patients with histologically confirmed adenocarcinoma or squamous cell carcinoma of the lung, for whom the primary curative approach was surgery, and who received no chemotherapy or radiotherapy prior to surgery. bFGF, VEGF, HGF were measured in extracts prepared from these 71 frozen tissue samples by ELISA. Five- and 10-year survival was obtained to determine the most important predictors of long-term survival. Among clinicopathological parameters, the mean concentration of bFGF was significantly higher in tissue extracts from cases involving metastatic nodal involvement (87.5+/-69.3 ng/100 mg protein) than in those without nodal involvement (57.6+/-42.5 ng; P<0.05). Levels of VEGF in adenocarcinoma (26.8+/-34.0 ng) were higher than for squamous cell carcinoma (12.2+/-13.8 ng; P<0.05). HGF levels also demonstrated histological differences (14.7+/-7.7 vs. 10.6+/-9.7 ng, P<0.05). bFGF protein levels were basically the same, but showed no statistically significant differences with respect to histological type (72.5+/-55.2 vs. 63.6+/-51.5 ng). Patients with high levels of bFGF or VEGF showed significantly worse survival rates than patients with low levels (P=0.0059; P=0.0134). In particular, high concentrations of both bFGF and VEGF correlated with markedly poor prognosis (P<0.0001). Multivariate analysis indicated that lymph node involvement and levels of bFGF and VEGF were independent prognostic factors in cases of NSCLC (adenocarcinoma or squamous cell carcinoma) involving patients who had undergone curative resection. Adenocarcinoma associated with lung cancer is regarded to have biological characteristics that distinguish it from squamous cell carcinoma. Node invasion may be associated with bFGF. bFGF and VEGF augment each other and are associated with leading to poor prognosis. The results of this study suggests that effective therapy to block angiogenesis may need to address at least both of these factors in cases of NSCLC.

Thalidomide and Thrombosis

Department of Hematology, San Bortolo Hospital Via Rodolfi – 36100 Vicenza (Italy) Tel. 39 0444 99 3626, Fax 39 0444 92 0708 E-Mail rodeghiero@hemato.ven.it Thalidomide is a glutamic acid derivative that exerts potent anti-angiogenic activity, modulation of T-cell activity and direct effects on tumour cells and their microenvironment. For its anti-inflammatory activity, mainly due to inhibition of TNFproduction, this agent is used to treat leprosy (registered use), lupus erythematosus, atopic dermatitis and Behcet’s disease. The anti-angiogenic activity of thalidomide suggested its use for the treatment of both solid and hematologic malignancies. Elevated levels of proangiogenic factors, particularly vascular endothelial growth factor (VEGF) have been associated with a poor prognosis in leukemias, multiple myeloma and NHL. In addition, a direct relationship between VEGF production and leukemic blasts and malignant plasma cells proliferation has been established, thus anti-VEGF agents are being evaluated in many protocols. The anti-angiogenic activity of the drug may be due to a reduction of both VEGF and b-FGF (basic fibroblast growth factor) levels, although disconcordant findings have been reported [1]. Thalidomide was shown to be effective in relapsed or refractory multiple myeloma and its role as part of the initial treatment armamentarium is under investigation. The anti-myeloma effect is mediated by several mechanisms: induction of G1 growth arrest/apoptosis by inhibiting NFB and activating caspase 8; inhibition of adhesion of myeloma cells to bone marrow stromal cells; inhibition of secretion of cytokines (TNF, IL-6, IL-1 ); induction of T cell and NK cell anti-myeloma immunity and inhibition of angiogenesis. Incidence of Thalidomide-Associated Thrombosis

Deficiency of the cysteine protease cathepsin S impairs microvessel growth.

During angiogenesis, microvascular endothelial cells (ECs) secrete proteinases that permit penetration of the vascular basement membrane as well as the interstitial extracellular matrix. This study tested the hypothesis that cathepsin S (Cat S) contributes to angiogenesis. Treatment of cultured ECs with inflammatory cytokines or angiogenic factors stimulated the expression of Cat S, whereas inhibition of Cat S activity reduced microtubule formation by impairing cell invasion. ECs from Cat S-deficient mice showed reduced collagenolytic activity and impaired invasion of collagens type I and IV. Cat S-deficient mice displayed defective microvessel development during wound repair. This abnormal angiogenesis occurred despite normal vascular endothelial growth factor and basic fibroblast growth factor levels, implying an essential role for extracellular matrix degradation by Cat S during microvessel formation. These results demonstrate a novel function of endothelium-derived Cat S in angiogenesis.

Granulocyte colony-stimulating factor may promote proliferation of human bladder cancer cells mediated by basic fibroblast growth factor.

To investigate whether granulocyte colony-stimulating factor (G-CSF) promotes the proliferation of two bladder cancer cell lines, and to assess the mechanism of tumor proliferation in terms of cytokine expression. The proliferation of two bladder cancer cell lines derived from transitional cell carcinoma (KK-47 and T-24) was assessed by using the double-layer soft agarose colony assay in combination with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Seven cytokines were measured in the culture supernatant. Expression of granulocyte colony-stimulating factor (G-CSF) receptor and fibroblast growth factor (FGF) receptor mRNA was studied by means of reverse transcriptase polymerase chain reaction (RT-PCR). Recombinant human G-CSF (rhG-CSF) caused greater induction of the proliferation of KK-47 cells in the presence than in the absence of peripheral blood mononuclear cells (PBMCs) and its effect was dose-dependent. In contrast, rhG-CSF did not stimulate the proliferation of T-24 cells. Among several cytokines measured, only basic FGF was elevated in cultures of KK-47 cells with or without PBMCs. The basic FGF level was significantly increased by rhG-CSF stimulation in a dose-dependent manner. Specific PCR products for the G-CSF and FGF receptors were observed in KK-47 cells as well as PBMC, while no G-CSF receptor was detected in T-24 cells. rhG-CSF may promote the proliferation of KK-47 cells, probably via an increase in basic FGF production.

Serum endostatin predicts tumor vascularity in hepatocellular carcinoma.

Tumor angiogenesis is a strong prognostic factor in patients with hepatocellular carcinoma (HCC). However, to the authors' knowledge, details regarding the serum levels of proangiogenic and antiangiogenic growth factors controlling this process are not yet known. Serum endostatin, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) levels were measured by the enzyme immunoassay method in prospectively collected samples from 33 HCC patients who had received no preoperative therapy. The angiogenic score (AS) and endostatin localization were evaluated using immunohistochemistry. Significant decreases in serum endostatin (P = 0.0007) and bFGF (P = 0.0004) were observed in postoperative samples compared with the preoperative values. A very strong direct correlation was noted between VEGF and endostatin (P < 0.0001). Only the preoperative serum endostatin was found to have a significant (P = 0.0025) inverse correlation with the AS. Furthermore, the combined positivity for bFGF and VEGF and negativity for endostatin was found to have a significantly (P = 0.0069) positive correlation with AS. Significantly high levels of endostatin were noted in patients with trabecular-type tumors (P = 0.0446) and in patients with hepatitis B infection (P = 0.0183). The serum endostatin level was found to be significantly (P = 0.0166) higher in living patients and patients with high serum endostatin levels had a tendency (P = 0.0871) toward long survival. Tissue endostatin expression was found to have a direct correlation with the serum endostatin level (P = 0.0117). The measurement of serum endostatin can predict tumor vascularity and may serve as a promising tool in the antiangiogenic therapy for patients with HCC.

Phase I Clinical Trial of Recombinant Human Endostatin Administered as a Short Intravenous Infusion Repeated Daily

To perform a phase I trial of recombinant human endostatin (rhEndostatin; EntreMed, Rockville, MD) given as a daily 20-minute intravenous (IV) injection in adult patients with refractory solid tumors. The daily dose was increased from 15 to 240 mg/m(2) by a factor of 100% in cohorts of three patients. In the absence of dose-limiting toxicity, uninterrupted treatment was continued until the tumor burden increased by more than 50% from baseline. Correlative studies included dynamic contrast-enhanced magnetic resonance imaging of tumor blood flow, urinary vascular endothelial growth factor and basic fibroblast growth factor levels, rhEndostatin serum pharmacokinetics, and monitoring of circulating antibodies to rhEndostatin. There were no notable treatment related toxicities among 15 patients receiving a total of 50 monthly cycles of rhEndostatin. One patient with a pancreatic neuroendocrine tumor had a minor response and two patients showed disease stabilization. Linearity in the pharmacokinetics of rhEndostatin was indicated by dose-proportionate increases in the area under the curve for the first dose and the peak serum concentration at steady state. Daily systemic exposure to rhEndostatin in patients receiving 240 mg/m(2)/d was approximately 50% lower than that provided by the therapeutically optimal dose in preclinical studies. rhEndostatin administered as a 20-minute daily IV injection at doses up to 240 mg/m(2) showed no significant toxicities. Evidence of clinical benefit was observed in three patients. Due to high variability between the peak and trough serum concentrations associated with the repeated short IV infusion schedule, daily serum drug levels only briefly exceeded concentrations necessary for in vitro antiangiogenic effects.

Inhibition of fibroblast growth factors by green tea

Investigators have shown that green tea may decrease the risk of cancer. It is widely accepted that the main active component of green tea is EGCG (epigallocatechin-3-gallate). In our previous study, we examined the effect of green tea on breast cancer growth and endothelial cells both in in vitro assays and in animal models. Our data show that both mixed green tea extract (GTE) as well as its individual catechin components are effective in inhibiting breast cancer and endothelial cell proliferation in vitro, and that GTE suppresses breast cancer xenograft size and decreases the tumor blood vessel density in vivo. In the present study, we further demonstrate that 40 microg/ml GTE or EGCG can decrease the levels of the angiogenic factor bFGF (basic fibroblast growth factor) levels in the cells. This phenomenon is observed in both human umbilical vein endothelial cells (HUVECs) and in human breast cancer cells MDA-MB231. This effect is dose dependent. Furthermore, GTE and EGCG decrease the transcript levels of bFGF and aFGF (acidic fibroblast growth factor) in HUVECs and MDA-MB231 cells. Our findings suggest that the inhibition of the angiogenic fibroblast growth factors could account for one of the mechanisms of green tea's actions. Since cancer is angiogenesis dependent, this may partially explain the antineoplastic effects associated with green tea consumption.

High Basic Fibroblast Growth Factor Levels in Nipple Aspirate Fluid Are Correlated with Breast Cancer

The angiogenic basic fibroblast growth factor (bFGF) and vascular endothelial growth factor are important in malignant breast epithelial growth. Nipple aspirate fluid (NAF) is a physiologic fluid collected noninvasively that contains proteins secreted by the breast ductal epithelium and may contain markers of breast cancer. The purpose of this study was to determine whether high concentrations of bFGF and vascular endothelial growth factor in NAF would be associated with in situ and invasive breast cancer, and whether prostate-specific antigen, a marker in NAF associated with breast cancer, would improve our ability to determine which subjects had the disease. Both bivariate and multivariate analyses were performed to determine the effects of race, menopausal status, bFGF concentration, and prostate-specific antigen on cancer risk. Bivariate analysis was also performed to determine the relationship between vascular endothelial growth factor concentration and cancer risk. Mean NAF bFGF levels were higher in women with breast cancer than in those without (19.2 vs 1.74 ng/g). Vascular endothelial growth factor was not associated with breast cancer. Race and menopausal status did not significantly affect the relationship between bFGF and cancer risk. bFGF, race, and menopausal status were each independent predictors of breast cancer, with bFGF being the most important. With knowledge of all three variables, the model was 89.9% sensitive and 69.0% specific in predicting which women had breast cancer. Adding prostate-specific antigen increased the sensitivity to 90.9% and the specificity to 83.3%. In subjects with NAF bFGF > 150 ng/g and prostate-specific antigen < 100 ng/g, 94.1% (32/34) of subjects had cancer. For women with NAF prostate-specific antigen > 100 ng/ g and bFGF < 150 ng/g, 90.5% were cancer free. bFGF concentration in NAF is directly associated with breast cancer, regardless of race and menopausal status. NAF bFGF may prove helpful in the early detection of breast cancer.

Phase II trial of thalidomide in renal-cell carcinoma

BackgroundThalidomide has been reported to yield anti-tumor activity in cancer. We performed a phase II trial of this drug in patients with metastatic renal cell carcinoma to determine its efficacy. Patients and methodsPatients with proven metastatic renal cell cancer, measurable progressive disease and a performance status of 0–2 were enrolled in this study. Thalidomide was given daily at a starting dose of 400 mg, followed by a 400 mg increment to 800 mg and then to 1200 mg with6–12 weeks at each dose level. The response rate at 6 months was the primary end point. Toxicity, overall survival, tumor vascularization depicted on color Doppler ultrasonography and serum vascular endothelial growth factor, basic fibroblast growth factor, interleukin-12 and tumor necrosis factor-α levels were secondary end points. ResultsForty patients were enrolled. Two partial responses were observed (5%) and disease remained stable in nine patients after 6 months. Median survival was 10 months. Toxicity was high, with frequent manifestations of fatigue, constipation and lethargy. The incidence of neuropathy detected on electromyography (EMG) attained 70% at 6 months, and 100% in patients on thalidomide for 12 months. Nine patients developed venous thromboembolism during the first 12 weeks of treatment, and three of them experienced pulmonary embolism. One unexpected (and unexplained) death occurred. ConclusionsDespite undisputed, albeit marginal, activity in renal cell cancer, high-dose thalidomide cannot be recommended using this schedule since the level of toxicity is high.

Expression of basic fibroblast growth factor is associated with poor outcome in non-Hodgkin's lymphoma.

It is now clear that angiogenesis and angiogenesis factors are important in the pathogenesis of haematological malignancies. High pretreatment levels of serum basic fibroblast growth factor have been shown to be associated with poor prognosis in patients with non-Hodgkin's lymphoma. The aim of this study was to evaluate whether non-Hodgkin's lymphoma cells express basic fibroblast growth factor and/or its receptor (fibroblast growth factor receptor-1) and whether basic fibroblast growth factor expression correlates with basic fibroblast growth factor serum levels, intratumoral microvessel density, and patient outcome. We measured basic fibroblast growth factor by enzyme-linked immunosorbent assay in sera taken from 58 patients with non-Hodgkin's lymphoma before treatment and in 19 of them also after treatment. Pathological specimens at diagnosis were evaluated by immunohistochemistry staining using polyoclonal antibody against factor-VIII-related antigen, basic fibroblast growth factor and fibroblast growth factor receptor-1 to determine the expression of the microvessel count and basic fibroblast growth factor and fibroblast growth factor receptor-1. The lymphoma specimens demonstrated positive staining for basic fibroblast growth factor (in 23%) and fibroblast growth factor receptor-1 (in 58.5%). The patients who expressed basic fibroblast growth factor had a significantly worse progression-free and overall survival than those who did not (P=0.003 and P=0.03 respectively), while patients expressing fibroblast growth factor receptor-1 were less likely to achieve complete remission than those lacking the receptor (33% vs 65% , P=0.047). There was no correlation of basic fibroblast growth factor staining with either serum basic fibroblast growth factor levels or microvessel count. Basic fibroblast growth factor serum levels did not change significantly after treatment These results suggest that non-Hodgkin's lymphoma specimens express basic fibroblast growth factor and its receptor (fibroblast growth factor receptor-1) and this expression is associated with poor patient outcome.British Journal of Cancer (2002) 86, 1770–1775. doi:10.1038/sj.bjc.6600330 www.bjcancer.com© 2002 Cancer Research UK

Effect of manipulation of primary tumour vascularity on metastasis in an adenocarcinoma model.

One explanation for the clinical association between tumour vascularity and probability of metastasis is that increased primary tumour vascularity enhances haematogenous dissemination by offering greater opportunity for tumour cell invasion into the circulation (intravasation). We devised an experimental tumour metastasis model that allowed manipulation of primary tumour vascularity with differential exposure of the primary and metastatic tumour site to angiogenic agents. We used this model to assess the effects of local and systemic increases in the level of the angiogenic agent basic fibroblast growth factor on metastasis. BDIX rats with implanted hind limb K12/TR adenocarcinoma tumours received either intratumoural or systemic, basic fibroblast growth factor or saline infusion. Both intratumoural and systemic basic fibroblast growth factor infusion resulted in significant increases in tumour vascularity, blood flow and growth, but not lung metastasis, compared with saline-infused controls. Raised basic fibroblast growth factor levels and increase in primary tumour vascularity did not increase metastasis. The clinical association between tumour vascularity and metastasis is most likely to arise from a metastatic tumour genotype that links increased tumour vascularity with greater metastatic potential.British Journal of Cancer (2002) 86, 123–129. DOI: 10.1038/sj/bjc/6600020 www.bjcancer.com© 2002 The Cancer Research Campaign

Increased aqueous humor basic fibroblast growth factor and hyaluronan levels in relation to the exfoliation syndrome and exfoliative glaucoma

To quantify the concentrations of basic fibroblast growth factor (bFGF) and hyaluronan (HA) in the aqueous humor of patients with the exfoliation syndrome (XFS) or exfoliative glaucoma (XFG). Aqueous humor bFGF and HA levels were measured in 13 patients with XFS and in 7 patients with XFG. The results were compared with those obtained from 17 healthy controls. Mean bFGF levels were significantly higher in the XFG patients than those in the XFS patients, which in turn were higher than the bFGF levels in the healthy individuals. Aqueous humor HA levels in both patients with the XFS and the XFG were significantly higher compared to the controls. We suggest that bFGF plays an important role in the pathogenesis of XFS and XFG, as well as in the synthesis of secreted HA, which may result in connective tissue degradation that affects the ocular anterior segment.