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Biomedical subjects

Giuseppe Giaccone

Publications and source records attributed to Giuseppe Giaccone.

At least 19 recordsLinked to original sources
PubMed2003

Polarization of Valpha24+ Vbeta11+ natural killer T cells of healthy volunteers and cancer patients using alpha-galactosylceramide-loaded and environmentally instructed dendritic cells.

CD1d-restricted natural killer T (NKT) cells play important regulatory roles in various immune responses. NKT cell-derived T helper (Th) 1 cytokines are important in the induction of antitumor immune responses in mice. Because the CD1d-restricted Valpha24(+) Vbeta11(+) NKT cell population in cancer patients is decreased both in size and in its capacity to secrete IFN-gamma, therapeutic strategies based on reconstitution of type 1 polarized Valpha24(+) Vbeta11(+) NKT cells merit additional investigation. Here, we report the simultaneous strong expansion and type 1 polarization of human invariant Valpha24(+) Vbeta11(+) NKT cells using alpha-galactosylceramide-loaded type 1 dendritic cells and interleukin 15. Type 1 polarized Valpha24(+) Vbeta11(+) NKT cells produced high levels of IFN-gamma, tumor necrosis factor alpha, and granulocyte macrophage colony-stimulating factor, and induced strong cytotoxicity in Jurkat cells in an alpha-galactosylceramide-dependent manner. Importantly, the cytokine profile of Valpha24(+) Vbeta11(+) NKT cells that were initially expanded under Th2 polarizing conditions could be reversed to a Th1 cytokine profile, indicating the plasticity of the cytokine profile of the human adult Valpha24(+) Vbeta11(+) NKT cell population.

Adult↗
PubMed2003

Subcellular localization of CrmA: identification of a novel leucine-rich nuclear export signal conserved in anti-apoptotic serpins.

The cowpox virus-encoded anti-apoptotic protein cytokine response modifier A (CrmA) is a member of the serpin family that specifically inhibits the cellular proteins caspase 1, caspase 8 and granzyme B. In this study, we have used Flag- and yellow fluorescent protein (YFP)-tagged versions of CrmA to investigate the mechanisms that regulate its subcellular localization. We show that CrmA can actively enter and exit the nucleus and we demonstrate the role of the nuclear export receptor CRM1 in this shuttling process. CrmA contains a novel leucine-rich nuclear export signal (NES) that is functionally conserved in the anti-apoptotic cellular serpin PI-9. Besides this leucine-rich export signal, additional sequences mapping to a 103-amino-acid region flanking the NES contribute to the CRM1-dependent nuclear export of CrmA. Although YFP-tagged CrmA is primarily located in the cytoplasm, shifting its localization to be predominantly nuclear by fusion of a heterologous nuclear localization signal did not impair its ability to prevent Fas-induced apoptosis. We propose that nucleocytoplasmic shuttling would allow CrmA to efficiently target cellular pro-apoptotic proteins not only in the cytoplasm, but also in the nucleus, and thus to carry out its anti-apoptotic function in both compartments.

Amino Acid Sequence↗
PubMed2003

Cisplatin triggers apoptotic or nonapoptotic cell death in Fanconi anemia lymphoblasts in a concentration-dependent manner.

Cells derived from Fanconi anemia (FA) patients are hypersensitive for cross-linking agents, such as cisplatin, that are potent inducers of programmed cell death (PCD). Here, we studied cisplatin hypersensitivity in FA in relation to the mechanism of PCD in lymphoblastoid cells representing FA groups A and C. In FA cells, a low concentration of cisplatin caused chromatin condensation, phosphatidylserine (PS) externalization, and the expression of an 18-kDa variant of Bax, all indicators of apoptotic cell death, and the latter suggesting the involvement of a mitochondrial route. However, procaspases-3, -8, and -9, and PARP were not cleaved, although small increases in caspase activity could be detected. At a high concentration of cisplatin, both FA and corrected cells showed a robust cleavage of procaspases and PARP. DNA fragmentation was clearly visible under high cisplatin conditions and to some extent at a low concentration in FA-A cells, but not in the FA-C cell line regardless of the presence of functional FANCC, suggesting an unknown deficiency in these cells. We conclude that hypersensitivity in FA cells is associated with a mixture of necrotic and apoptotic features that is best described as apoptotic-like cell death, and that a defective FA pathway does not interfere with the proper activation of caspase-mediated cell death.

Apoptosis↗
PubMed2003

Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected].

PURPOSE: To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomly assigned to receive either 250-mg or 500-mg oral doses of gefitinib once daily. RESULTS: Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively. CONCLUSION: Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC [corrected]

Administration, Oral↗
PubMed2003

Ongoing and future trials of biologic therapies in lung cancer.

Lung cancer is the leading world-wide cause of cancer death. The care rate remains less than 15% despite improvements in surgery, radiotherapy and chemotherapy. The majority of deaths can be attributed to systemic metastases. Chemotherapy prolongs survival but produces few complete responses and survival at 5-years is rare. Molecular advances have provided many new targets for lung cancer therapy. Many new agents have been developed to attack these targets. This article describes current and proposed trials for these new targeted therapies in both small cell and non-small cell lung cancers.

Adult↗
PubMed2003

Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways.

The epidermal growth factor receptor (EGFR) is an important novel target for anticancer therapy. In this study, we examined the molecular mechanisms that underlie the antitumor effects of the anti-EGFR monoclonal antibody C225 (Cetuximab) and the selective EGFR tyrosine kinase inhibitor ZD1839 (Iressa; AstraZeneca) in non-small cell lung cancer (NSCLC) cell lines. Cell growth, assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, was inhibited at low concentrations of ZD1839 and C225 in control A431 cells, whereas the NSCLC cell lines were comparatively more resistant. In A431 cells, but not in the NSCLC cells, ZD1839 treatment resulted in a modest increase in DNA fragmentation, the externalization of phosphatidyl serine, and the activation of caspase-3, known markers of apoptotic cell death. However, poly(ADP-ribose) polymerase cleavage was not detected, and caspase inhibition by carbobenzoxy-Val-Ala-Asp-fluoromethyl ketone partially reduced ZD1839-generated DNA fragmentation. Overexpression of the antiapoptotic protein Bcl-2 in A431 cells suppressed the cytotoxicity upon anti-EGFR treatment. These results thus demonstrate that the toxic effect of ZD1839 in A431 cells is caused by a form of cell death that involves a mitochondrial step and is, at least in part, dependent on caspase activation. EGFR expression levels showed no significant correlation with sensitivity to ZD1839 and C225. Evaluation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase and phosphatidylinositol 3'-kinase/Akt pathways showed considerable inhibition of these pathways by ZD1839 and C225 in A431 cells, whereas one or both of these pathways remained active upon anti-EGFR treatment in NSCLC cells. In addition, treatment with specific inhibitors of mitogen-activated protein kinase kinase or phosphatidylinositol 3'-kinase resulted in a smaller effect on proliferation than simultaneous treatment with both inhibitors, whereas induction of apoptosis was observed only when both pathways were blocked. Together, these data suggest that persistent activity of either of these signaling pathways is involved in the lack of sensitivity of NSCLC cell lines to EGFR inhibitors.

Antibodies, Monoclonal↗
PubMed2002

Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of Cancer.

PURPOSE: Increased expression of metalloproteinases is associated with poor prognosis in small-cell lung cancer (SCLC). This trial was undertaken to determine whether adjuvant treatment with the metalloproteinase inhibitor marimastat could prolong survival in responding patients with SCLC after chemotherapy. PATIENTS AND METHODS: SCLC patients in complete or partial remission were eligible. They were stratified by radiotherapy (early, late, or none), stage (extensive or limited), response (complete or partial), and cooperative group (National Cancer Institute of Canada-Clinical Trials Group or European Organization for Research and Treatment of Cancer). They were randomized to receive marimastat 10 mg or placebo orally bid for up to 2 years. RESULTS: There were 532 eligible patients (266 marimastat and 266 placebo). Stage was limited for 279 patients (52%) and extensive for 253 (48%). Best response to induction therapy was complete remission for 176 patients (33%), partial remission for 341 (64%), and 15 patients (3%) had undergone surgical resection. The median time to progression for marimastat patients was 4.3 months compared with 4.4 months for placebo patients (P =.81). Median survivals for marimastat and placebo patients were 9.3 months and 9.7 months, respectively (P =.90) Toxicity was generally limited to musculoskeletal symptoms (18% grade 3/4 for marimastat). Dose modifications for musculoskeletal toxicity were required in 90 patients (33%) on the marimastat arm, and 87 (32%) permanently stopped marimastat because of toxicity. Patients on marimastat had significantly poorer quality of life at 3 and 6 months. CONCLUSION: Treatment with marimastat after induction therapy for SCLC did not result in improved survival and had a negative impact on quality of life.

Adult↗
PubMed2002

Clinical impact of novel treatment strategies.

Following two decades of research on the biology of cancer and in particular of lung cancer, we have now a large number of molecular targets that can be utilized to create specific medicines against these cancers. Non-small cell lung cancer represents numerically the most important solid tumor in Western world, and is poorly affected by current therapies, where surgery represents almost the only curative therapy for about 25% of patients who are resectable at diagnosis. An abundant number of targeted therapies are being investigated in NSCLC. Among them are the metalloproteinase inhibitors, several tyrosine kinase inhibitors and several attempts of gene replacement have also been made. Promising results have so far been obtained with some of these approaches, and the outcome of large randomized studies is awaited. Small cell lung cancer (SCLC) represents about 20% of lung carcinomas, and several of the novel approaches that are being attempted for NSCLC, are also being investigated for SCLC. All these novel therapies open a new era of anticancer treatment that will likely complement the currently available therapies in the near future.

Antibodies, Monoclonal↗
PubMed2002

Standard versus intensified chemotherapy with granulocyte colony-stimulating factor support in small-cell lung cancer: a prospective European Organization for Research and Treatment of Cancer-Lung Cancer Group Phase III Trial-08923.

PURPOSE: To assess the impact on survival of increasing dose-intensity (DI) of cyclophosphamide, doxorubicin, and etoposide (CDE) in small-cell lung cancer (SCLC). PATIENTS AND METHODS: Previously untreated SCLC patients were randomized to standard CDE (cyclophosphamide 1,000 mg/m(2) and doxorubicin 45 mg/m(2) on day 1, and etoposide 100 mg/m(2) on days 1 to 3 every 3 weeks, for five cycles) or intensified CDE (cyclophosphamide 1,250 mg/m(2) and doxorubicin 55 mg/m(2) on day 1, and etoposide 125 mg/m(2) on days 1 to 3 with granulocyte colony-stimulating factor [G-CSF] 5 micro g/kg/d on days 4 to 13 every 2 weeks, for four cycles). Projected cumulative dose was almost identical on the two arms, whereas projected DI was nearly 90% higher on the intensified arm. Two hundred forty-four patients were enrolled. The first 163 patients were also randomized (2 x 2 factorial design) to prophylactic antibiotics or placebo to assess their impact on preventing febrile leukopenia (FL). This report focuses on chemotherapy DI results. RESULTS: With a median follow-up of 54 months, 216 deaths have occurred. Actually delivered DI on the intensified arm was 70% higher than on the standard arm. Intensified CDE was associated with more grade 4 leukopenia (79% v 50%), grade 4 thrombocytopenia (44% v 11%), anorexia, nausea, and mucositis. FL and number of toxic deaths were similar on the two arms. The objective response rate was 79% for the standard arm and 84% for the intensified arm (P =.315). Median survival was 54 weeks and 52 weeks, and the 2-year survival rates were 15% and 18%, respectively (P =.885). CONCLUSION: A 70% increase of CDE actual DI does not translate into an improved outcome in SCLC patients.

Adult↗
PubMed2002

Late activation of apoptotic pathways plays a negligible role in mediating the cytotoxic effects of discodermolide and epothilone B in non-small cell lung cancer cells.

Discodermolide and epothilone B are promising novel chemotherapeutic agentsthat induce cell death through potent stabilization of microtubules. In this study, we investigated the cellular and molecular events underlying the cytotoxicity of these drugs in non-small cell lung carcinoma (NSCLC) cell lines, focusing on apoptotic characteristics. IC80 concentrations of either drug effectively disrupted the microtubule cytoskeleton of H460 cells and induced cell cycle disturbances with early accumulation in the G2-M phase and development of a hypodiploid cell population in both H460 and SW1573 cells. These events were followed by abnormal chromosome segregation during mitosis and subsequent appearance of multinucleated cells. At later time points, the cells displayed several apoptotic features, such as nuclear condensation and fragmentation as well as Annexin V staining, cleavage of poly(ADP-ribose) polymerase and the activation of caspases. To examine the contribution of apoptotic pathways to the cytotoxic effects of these agents, the involvement of the mitochondria and death receptor routes was studied. At 48 h after treatment, both agents disrupted mitochondria of H460 cells, as indicated by cytochrome c release. Nonetheless, H460 cells stably overexpressing antiapoptotic Bcl-2 or Bcl-xL did not show any protective effect from cell death induced by either drug. Possible death receptor dependency was investigated in H460 cells stably overexpressing dominant-negative FADD, which failed to reduce the cytotoxic effects of discodermolide and epothilone B. To study the role of caspases more directly, the effect of stable overexpression of the caspase-8 inhibitor cytokine response modifier A was studied in H460 cells. Furthermore, the effect of the pancaspase inhibitor z-Val-Ala-Asp-fluoromethyl ketone was investigated in a panel of lung carcinoma cell lines. Interestingly, caspase inhibition did not rescue cells from discodermolide or epothilone B-induced cell death. In conclusion, these results demonstrate that despite several apoptotic features detected at relatively late time points after drug exposure, apoptosis is not the dominant mode of cell death and induced low but efficacious concentrations of discodermolide and epothilone B.

Alkanes↗
PubMed2002

CRM1-mediated nuclear export determines the cytoplasmic localization of the antiapoptotic protein Survivin.

Survivin is a member of the inhibitor of apoptosis (IAP) family of negative regulators of programmed cell death that is frequently overexpressed in human tumors. Survivin is not only involved in the regulation of apoptosis, but is also known to play a role in the control of cell cycle progression at the G2/M phase. Survivin is a predominantly cytoplasmic protein expressed in a cell cycle-dependent manner, but the mechanism(s) that determine its nuclear-cytoplasmic localization have not been described. In this study, we report that Survivin is a nuclear shuttling protein that is actively exported from the nucleus via the CRM1-dependent pathway. Nuclear export of Survivin is independent of the export of other shuttling proteins that control the G2/M phase transition, such as cyclin B1 and cdc25. The carboxy-terminal domain of Survivin is both necessary and sufficient for its nuclear export, although this region does not contain a functional leucine-rich nuclear export signal. Differences in the amino acid sequence of this region determine the dramatically different localization of Survivin (in the cytoplasm) and its splicing variant Survivin-DeltaEx3 (in the nucleus). The carboxy-terminal end of Survivin-DeltaEx3 contains a bipartite nuclear localization signal, not present in Survivin, which mediates its strong nuclear accumulation. These data suggest that active transport between the nucleus and cytoplasm may constitute an important regulatory mechanism for Survivin function.

Alternative Splicing↗
PubMed2002

Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors.

PURPOSE: To investigate the feasibility and pharmacokinetics of the combination cisplatin, gemcitabine, and SU5416. PATIENTS AND METHODS: Patients received cisplatin 80 mg/m(2) on day 1, gemcitabine 1,250 mg/m(2) on days 1 and 8, repeated every 3 weeks, and SU5416 (85 and 145 mg/m(2)) intravenously twice weekly. Pharmacokinetics of all three agents, side effects, and antitumor response were investigated in patients with solid tumors amenable to therapy with cisplatin/gemcitabine. RESULTS: In the first cohort of three patients entered at the 85 mg/m(2) dose, no dose-limiting toxicities were observed. In the next cohort (145 mg/m(2)), three patients developed a thromboembolic event. After entry was restricted to patients with low thromboembolic risk, three additional patients enrolled at 145 mg/m(2) developed a thromboembolic event. The dose was then reduced to 85 mg/m(2) in all patients still on the study, and three additional patients were entered on this dose level. In 19 treated patients, eight patients developed nine thromboembolic events (three transient ischemic attacks, two cerebrovascular accidents, and four deep venous thromboses). The most common toxicities observed were those previously reported for SU5416 alone (headache and phlebitis) and for this chemotherapy regimen (nausea, thrombocytopenia, and leucopenia). No significant pharmacologic interaction among the three drugs was observed. Response rates were similar to those expected in the patient population selected for this study. Analysis of variables of the coagulation cascade and of vessel wall activation was performed in three patients and showed significant increases in thrombin generation and endothelial cell perturbation in a treatment cycle-dependent manner. CONCLUSION: The incidence of thromboembolic events, possibly related to the particular regimen tested in this study, discourages further investigation of this regimen.

Adult↗
PubMed2002

Selective decrease in circulating V alpha 24+V beta 11+ NKT cells during HIV type 1 infection.

CD1d-restricted NKT cells express an invariant TCR and have been demonstrated to play an important regulatory role in a variety of immune responses. Invariant NKT cells down-regulate autoimmune responses by production of type 2 cytokines and can initiate antitumor and antimicrobial immune responses by production of type 1 cytokines. Although defects in the (invariant) Valpha24+Vbeta11+ NKT cell population have been observed in patients with cancer and autoimmune diseases, little is known regarding the protective role of Valpha24+Vbeta11+ NKT cells in human infectious disease. In a cross-sectional study in HIV-1-infected individuals, we found circulating numbers of Valpha24+Vbeta11+ NKT cells to be reduced, independent of CD4+ T cell counts, CD4:CD8 ratios, and viral load. Because a small minority of Valpha24+Vbeta11+ NKT cells of healthy donors expressed HIV-1 (co)receptors and the vast majority of Valpha24+Vbeta11+ NKT cells in HIV-1-infected individuals expressed the Fas receptor, the depletion was more likely due to Fas-mediated apoptosis than to preferential infection of Valpha24+Vbeta11+ NKT cells by HIV-1. A longitudinal cohort study, in which patients were analyzed before seroconversion and 1 and 5 years after seroconversion, demonstrated that a large proportion of the depletion occurred within the first year postseroconversion. In this longitudinal study no evidence was found to support an important role of Valpha24+Vbeta11+ NKT cells in determining the rate of progression during HIV-1 infection.

Adult↗
PubMed2002

Population pharmacokinetics of the novel anticancer agent KRN7000.

PURPOSE: KRN7000 is a novel anticancer agent, acting through stimulation of the immune system. The first clinical trial with this agent, which included pharmacokinetic studies, has recently been completed. The aim of the study presented here was to develop a population pharmacokinetic model for KRN7000. METHODS: Plasma concentration-time data were gathered from 24 patients enrolled in a phase I trial in which KRN7000 was administered as a weekly slow injection at doses ranging from 50 to 4800 microg/m(2). These data were used to build a pharmacokinetic model using the nonlinear mixed-effect modeling (NONMEM) program. The model was validated by performance of 200 bootstraps. RESULTS: A three-compartment model with interindividual variability on the central and two peripheral volumes of distribution (V1, V2 and V3) and on clearance (CL) adequately described the data. The final estimates were: V1 2.34 l, V2 2.61 l, V3 2.13 l, and CL 0.130 l/h. Of 24 covariates tested, including both demographic and pathophysiological factors, none showed a significant relationship with the pharmacokinetic parameters obtained. The bootstrap analysis provided parameter estimates within approximately 15% of the original estimates, indicating stability of the model. CONCLUSION: The pharmacokinetic behavior of KRN7000 in the clinical trial could be described by a three-compartment model. Hence, KRN7000 demonstrates linear pharmacokinetics over the investigated dose range. The pharmacokinetics of KRN7000 are not influenced by patient demographic or pathophysiological characteristics.

Adult↗
PubMed2002

Targeted therapy in non-small cell lung cancer.

Cytotoxic chemotherapy for advanced non-small cell lung cancer (NSCLC) offers only modest benefits over best supportive care alone by modestly prolonging survival, reducing symptoms, and improving quality of life. Despite the introduction of a number of new agents over the past decade, we have seen no convincing improvements in efficacy and safety with platinum-based regimens. It appears that a plateau has been reached in the development of traditional cytotoxic chemotherapy and a new paradigm is needed. Novel treatment modalities have emerged from advances in the understanding of tumor cell biology. These sophisticated new agents home in on and neutralize specific targets in the biologic pathway of cancer. This "targeted therapy" represents a new generation of anticancer treatment and a chance to revitalize the moribund state of NSCLC treatment.

Angiogenesis Inhibitors↗
PubMed2002

The role of new agents in the treatment of non-small cell lung cancer.

Lung cancer is one of the most frequent causes of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of cases and no curative treatment is available for the advanced stages of disease (stages III and IV), which comprise the majority of cases. Current treatment regimens with standard chemotherapy offer only a limited survival benefit, and, therefore, the development of new therapeutic strategies is needed. Novel chemotherapeutic drugs such as the epothilones, MEN 10755 and S-1 are being studied in patients with advanced stages of disease. Furthermore, a large number of therapies targeted against critical biological abnormalities in NSCLC are being investigated in clinical trials. The latter approach includes inhibition of growth factors, interference with abnormal signal transduction, inhibition of angiogenesis and gene replacement therapy. Promising results have thus far been obtained with some of these therapies. This review describes the role of new therapeutic agents in the treatment of NSCLC.

Alkyl and Aryl Transferases↗
PubMed2002

Novel approaches to the treatment of non-small cell lung cancer.

Prognosis of non-small cell lung carcinomas (NSCLC) remains poor, especially in advanced disease. The introduction of new cytotoxic agents in the past decade did only attain minor improvements in survival. It is rather clear that chemotherapy may have reached a plateau, and that it will be difficult to obtain better results in advanced NSCLC by chemotherapy alone. Novel treatment modalities are urgently needed in advanced NSCLC. Backed-up by advances in the understanding of tumor cell biology, a new generation of anticancer agents specifically directed at targets such as tyrosine kinases, farnesyl transferase, angiogenesis factors, matrixmetalloproteinases and oncogenes has been developed in recent years. In this review, we give a brief summary of the state-of-the-art treatment of NSCLC, highlighting its limitations. Novel systemic approaches are then discussed in detail with focus on their mechanistic rationale, stage of clinical development and possible drawbacks. Finally, perspectives of future applications and impact on the treatment of NSCLC are also discussed.

Angiogenesis Inhibitors↗