Disease relevance of Naganol

• Heparin, highly sulfated heparan sulfate, and the polysulfonate pharmaceutical Suramin effectively prevented dengue virus infection of target cells, indicating that the envelope protein-target cell receptor interaction is a critical determinant of infectivity [1].
• Here we show that suramin inhibits apoptosis induced through death receptors in hepatoma and lymphoma cells [2].
• Suramin also shows similar effects in in vivo models: apoptotic liver damage induced by CD95 stimulation and endotoxic shock mediated by tumor-necrosis factor (TNF) are inhibited in mice, but necrotic liver damage is not inhibited in a rat model of liver transplantation [2].
• Suramin has now been found to block in vitro the infectivity and cytopathic effect of HTLV-III at doses that are clinically attainable in human beings [3].
• Suramin is a drug used in the therapy of Rhodesian trypanosomiasis and onchocerciasis, and it is known to inhibit the reverse transcriptase of a number of retroviruses [3].

Psychiatry related information on Naganol

• Three patients, who received all 18 doses of suramin per protocol, developed severe, but not dose-limiting, malaise, fatigue, and lethargy [4].
• Effects of suramin on hippocampal apyrase activity and inhibitory avoidance learning of rats [5].
• Intrahippocampal infusion of suramin (0.01, 0.1, 1, and 10 microg) immediately posttraining, in a dose-dependent effect, significantly reduced the response latency during the retention test applied 24 h after the rats received step-down inhibitory avoidance training [5].
• Our results indicate that the polysulfonated naphthylurea suramin, a "non-specific drug" that interferes with multiple cellular proteins, inhibits neointimal formation in rabbit iliac arteries after balloon-catheter injury administered throughout the critical period of several weeks after the procedure [6].

High impact information on Naganol

• The UVC response is inhibited by prior down-modulation of growth factor receptor signaling upon growth factor prestimulation, by suramin (an inhibitor of receptor activation) or by expression of a dominant negative epidermal growth factor (EGF) receptor mutant [7].
• Suramin inhibits death receptor-induced apoptosis in vitro and fulminant apoptotic liver damage in mice [2].
• Interference with normal phagosome-lysosome fusion in macrophages, using ingested yeast cells and suramin [8].
• Suramin protection of T cells in vitro against infectivity and cytopathic effect of HTLV-III [3].
• Suramin sodium is a reverse transcriptase inhibitor with in vitro activity against the human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS) [9].

Chemical compound and disease context of Naganol

• Upon testing this hypothesis in prostate cancer cell lines, we found that the most conspicuous effect of suramin was to increase the tyrosine phosphorylation of several distinct proteins [10].
• BACKGROUND: The best treatment for patients with "hormone-refractory" metastatic prostate cancer is unclear, particularly in patients for whom suramin and hydrocortisone have failed [11].
• Synergistic activity of suramin with tumor necrosis factor alpha and doxorubicin on human prostate cancer cell lines [12].
• Suramin, 200 mg/kg i.v., inhibited rat corneal angiogenesis induced by bFGF-impregnated polymers; addition of heparin stimulated angiogenesis and counteracted the inhibition of suramin [13].
• Androgen deprivation and four courses of fixed-schedule suramin treatment in patients with newly diagnosed metastatic prostate cancer: A Southwest Oncology Group Study [14].

Biological context of Naganol

• Suramin has been shown to inhibit growth factor signaling pathways; however, its effect on apoptosis is unknown [2].
• When tumor cells were treated with NaPA together with suramin, a drug with demonstrable activity in patients, there was complete abrogation of cell growth under conditions in which each treatment alone produced only a partial effect [15].
• The fact that cell proliferation resumes when suramin is removed indicates that this is not a cytotoxic effect [16].
• Suramin treatment demonstrated continuous downregulation of the alpha receptor surface expression [17].
• Effects of suramin on HTLV-III/LAV infection presenting as Kaposi's sarcoma or AIDS-related complex: clinical pharmacology and suppression of virus replication in vivo [18].

Anatomical context of Naganol

• Previous studies have shown that suramin is capable of disrupting autocrine growth involving coexpression of platelet-derived growth factor and its receptors in a fibroblast model for mesenchymal oncogenesis [19].
• Suramin is currently in use as an experimental drug for the treatment of patients with epithelial cell tumors [19].
• RESULTS: With the use of the HTCA method, 80% or more of carcinomas of the colon, endometrium, kidney, lung (non-small-cell), and ovary as well as malignant melanoma and mesothelioma were sensitive to 200 micrograms/mL of suramin by continuous exposure [20].
• In the presence of hexamethonium, suramin (100 micromol/L) or the P2X antagonist pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS, 10 micromol/L) reduced the control fEPSP amplitude in the duodenum, ileum, taenia coli, proximal colon, and distal colon by 71%-84% [21].
• Suramin and eosinophil degranulation and vacuolation in onchocerciasis [22].

Associations of Naganol with other chemical compounds

• Since suramin potently blocks tyrosine phosphorylation induced by platelet-derived growth factor but can activate the growth pathway regulated by the EGFR, biological responses of tumor cells to suramin treatment may differ dramatically [19].
• All patients were taking flutamide at the time of entry, and previous treatments with medical or surgical castration, flutamide, suramin, and hydrocortisone had failed in all of these patients [11].
• In the androgen-sensitive LNCaP cells, however, transferrin had limited ability to block the inhibitory activity of suramin [23].
• Maximal inhibition was obtained after 5 days of suramin treatment, and inhibition either was partially reversed by E2, IGF-I, and IGF-II or was not reversible by EGF following removal of drug [24].
• PSA mRNA expression was assessed by northern blot analysis in cells treated with either 250 microgram/mL suramin, 400 ng/mL dihydrotestosterone (DHT) (positive control), or 0.5-75 microgram/mL hydrocortisone (to mimic the clinical use of hydrocortisone during suramin treatment to compensate for the loss of adrenocortical function) [25].
• This effect was significantly enhanced when suramin was combined with hyperoxia [26].
• When lysine was introduced into the mouse receptor, the sensitivity to block by suramin and NF449 was much increased for E138K, but not for Q111K, Q127K, or N148K [27].

Gene context of Naganol

• Treatment of the transformed transfected NIH 3T3 cells with suramin, which blocks the interaction of bFGF with its receptor, reversed the morphological transformation and restored receptors almost to normal numbers [28].
• Transformation of NIH 3T3 cells with basic fibroblast growth factor or the hst/K-fgf oncogene causes downregulation of the fibroblast growth factor receptor: reversal of morphological transformation and restoration of receptor number by suramin [28].
• HNP-induced IL-8 release was inhibited by treatment with the nucleotide receptor antagonists suramin and reactive blue [29].
• ERK activation by BHTOOH was inhibited by suramin, and by expression of dominant-negative Ras-N-17 in PC12 cells, suggesting overlap between the pathways for BHTOOH and growth factor signaling [30].
• Similarly, pretreatment with suramin or the MEK inhibitor PD098059 also potentiated the toxicity of BHTOOH [30].

Analytical, diagnostic and therapeutic context of Naganol

• Sixteen patients died while receiving suramin or within three weeks of discontinuation of drug therapy due to infection (n = 6), hepatic failure (n = 3), pulmonary Kaposi's sarcoma (n = 2), AIDS encephalitis (n = 2), AIDS-associated NHL (n = 1), iatrogenic hemo-pneumothorax (n = 1), or pulmonary disease of uncertain etiology [9].
• IMPLICATIONS: PSA level should be used with caution as an end point in clinical trials using suramin therapy for hormone-refractory prostate cancer [25].
• IMPLICATIONS: Future trials should address the role and necessary extent of therapeutic drug monitoring; the optimal plasma drug concentration range and duration of therapy; and the activity of suramin in combination with other agents, in earlier stages of prostate cancer, and in other tumor types [31].
• However, suramin significantly decreased the ratio of PSA level to tumor volume (ng/mL PSA per mm(3) of tumor) (P<.001) [25].
• BACKGROUND: Suramin, a polysulfonated naphthylurea and a recognized antitrypanosomal agent, has shown some promise in phase II clinical trials in the management of hormone-refractory human prostate cancer [25].

References