Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 5-year-old male presented with spinal cord drop metastasis from a recurrent neurocytoma. Topotecan (0.5 mg/m(2)) and carboplatin (250 mg/m(2)) were administered on days 1-3 and ifosfamide (1,800 mg/m(2)) on days 1-5, every 21 days, for three cycles and resulted in complete response without severe complications. A literature review yielded 20 patients with central neurocytoma but no complete responses. The complete response of central neurocytoma to chemotherapy only reported here should be helpful to those caring for patients with this rare tumor.
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PMID:Central neurocytoma responsive to topotecan, ifosfamide, carboplatin. 1833 96

Despite aggressive surgery, radiation therapy, and chemotherapy, glioblastoma multiforme (GBM) is refractory to therapy, recurs quickly, and results in a median survival time of only 14 months. The modulation of the apoptotic receptor Fas with cytotoxic agents could potentiate the response to therapy. However, Fas ligand (FasL) is not expressed in the brain and therefore this Fas-inducing cell death mechanism cannot be utilized. Vaccination of patients with gliomas has shown promising responses. In animal studies, brain tumors of vaccinated mice were infiltrated with activated T cells. Since activated immune cells express FasL, we hypothesized that combination of immunotherapy with chemotherapy can activate Fas signaling, which could be responsible for a synergistic or additive effect of the combination. When we treated the human glioma cell line U-87 and GBM tumor cells isolated from patients with TPT, Fas was up regulated. Subsequent administration of soluble Fas ligand (sFasL) to treated cells significantly increased their cell death indicating that these Fas receptors were functional. Similar effect was observed when CD3(+) T cells were used as a source of the FasL, indicating that the up regulated Fas expression on glioma cells increases their susceptibility to cytotoxic T cell killing. This additive effect was not observed when glioma cells were pre-treated with temozolomide, which was unable to increase Fas expression in tumor. Inhibition of FasL activity with the antagonistic antibody Nok-1 mitigated these effects confirming that these responses were specifically mediated by the Fas-FasL interaction. Furthermore, the CD3(+) T cells co-cultured with topotecan treated U-87 and autologous GBM tumor cells showed a significant increase in expression in IFN-gamma, a key cytokine produced by activated T cells, and accordingly enhanced tumor cytotoxicity. Based on our data we conclude that drugs, such as topotecan, which cause up regulation of Fas on glioma cells can be potentially exploited with immunotherapy to enhance immune clearance of tumors via Fas signaling.
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PMID:Topotecan enhances immune clearance of gliomas. 1859 17

Neuroblastoma produce angiogenic peptides, and the extent of angiogenesis correlates with tumor progression and poor clinical outcome. Hence, angiogenic factor inhibition represents an important therapeutic option. One of the major drives to tumor angiogenesis is hypoxia, a decrease in oxygen tension that characterizes the tumor microenvironment. We investigated the effects of the topoisomerase I inhibitor, topotecan, on vascular endothelial growth factor (VEGF) induction by hypoxia in advanced-stage human neuroblastoma cells. Topotecan counteracted hypoxic induction of VEGF and decreased angiogenic activity of conditioned medium from hypoxic cultures in vivo in the chick chorioallantoic membrane. Promoter-driven reporter studies showed the role of both hypoxia-inducible factor (HIF)-1alpha and -2alpha in VEGF transcription activation by hypoxia, because (a) overexpression of either protein by cotransfection with expression vectors resulted in VEGF promoter transactivation, which was abrogated by mutation in the HIF-binding site, and (b) targeted knockdown of HIF-1alpha/2alpha by RNA interference inhibited hypoxia-stimulated VEGF transcriptional activity and protein secretion. Topotecan-inhibitory effects on VEGF induction by hypoxia were mediated through suppression of both HIF-1alpha and HIF-2alpha protein accumulation and transactivation properties, which was specific and required ongoing RNA transcription. A similar pattern of results was obtained in cells treated with the hypoxia-mimetic agent, desferrioxamine. These data provide the first evidence that topotecan is a potent inhibitor of HIF-1alpha and HIF-2alpha subunits in hypoxic neuroblastoma cells, leading to decreased VEGF expression and angiogenic activity. An important clinical implication of these findings is that therapies targeted to the HIF pathway have the potential to inhibit neuroblastoma angiogenesis and growth.
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PMID:Topotecan inhibits vascular endothelial growth factor production and angiogenic activity induced by hypoxia in human neuroblastoma by targeting hypoxia-inducible factor-1alpha and -2alpha. 1864 7

The Werner syndrome helicase/3'-exonuclease (WRN) is a major component of the DNA repair and replication machinery. To analyze whether WRN is involved in the repair of topoisomerase-induced DNA damage we utilized U2-OS cells, in which WRN is stably down-regulated (wrn-kd), and the corresponding wild-type cells (wrn-wt). We show that cells not expressing WRN are hypersensitive to the toxic effect of the topoisomerase I inhibitor topotecan, but not to the topoisomerase II inhibitor etoposide. This was shown by mass survival assays, colony formation and induction of apoptosis. Upon topotecan treatment WRN deficient cells showed enhanced DNA replication inhibition and S-phase arrest, whereas after treatment with etoposide they showed the same cell cycle response as the wild-type. A considerable difference between WRN and wild-type cells was observed for DNA single- and double-strand break formation in response to topotecan. Topotecan induced DNA single-strand breaks 6h after treatment. In both wrn-wt and wrn-kd cells these breaks were repaired at similar kinetics. However, in wrn-kd but not wrn-wt cells they were converted into DNA double-strand breaks (DSBs) at high frequency, as shown by neutral comet assay and phosphorylation of H2AX. Our data provide evidence that WRN is involved in the repair of topoisomerase I, but not topoisomerase II-induced DNA damage, most likely via preventing the conversion of DNA single-strand breaks into DSBs during the resolution of stalled replication forks at topo I-DNA complexes. We suggest that the WRN status of tumor cells impacts anticancer therapy with topoisomerase I, but not topoisomerase II inhibitors.
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PMID:WRN protects against topo I but not topo II inhibitors by preventing DNA break formation. 1880 12

A series of E-ring gamma-lactone camptothecin derivatives were synthesized by semi-synthesis via a three-step domino reaction. Their biological activity was evaluated on two types of human tumor cell lines A549 and HT-29 with sulforhodamine-B (SRB) method. The antitumor activity of these compounds was lower than SN-38, only compound 12c was found to be close to the activity of Topotecan. The structure-activity relationship (SAR) of these analogs was studied and discussed.
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PMID:Semi-synthesis and biological activity of gamma-lactones analogs of camptothecin. 1898 7

Over 25,000 people are diagnosed with small-cell lung cancer (SCLC) in the United States annually. SCLC is a highly aggressive tumor with a propensity for early metastases and a high case-fatality rate. Systemic treatment with etoposide plus a platinum agent is recommended for all stages of this disease and has been a standard first-line therapy for SCLC since the 1980s. Three recently presented randomized clinical trials failed to show superiority of newer regimens over etoposide and cisplatin. Patients with limited-stage (LS) disease benefit from the addition of radiotherapy to systemic chemotherapy, a combination that affords high complete response rates and potential cures. Incremental improvements in radiotherapy delivery over the past decade include the use of accelerated hyperfractionated thoracic radiotherapy for LS disease. Prophylactic cranial irradiation, previously recommended for patients with LS disease, has recently been shown to benefit those with extensive-stage (ES) disease as well. Surgery, largely abandoned in the 1970s, is being reevaluated as primary local therapy in patients with very early-stage SCLC. Topotecan remains the only US Food and Drug Administration-approved therapy for recurrent disease. Amrubicin has demonstrated single-agent activity in multiple phase II trials in both chemotherapy-sensitive and -refractory relapse. The past 2 decades have been marked by an improved understanding of SCLC biology, and these discoveries are reflected in the number and diversity of novel therapies entering early-phase testing in this disease.
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PMID:Management of small-cell lung cancer: incremental changes but hope for the future. 1922 72

Chemotherapy of brain tumors remains a big challenge owing to the low drug transport across the blood-brain barrier (BBB), multidrug resistance (MDR), and poor penetration into the tumor tissue. We developed a novel dual-targeting liposomal carrier that enabled drug to transport across the BBB and then target the brain tumor. In the dual-targeting liposomal carrier, tamoxifen (TAM) was incorporated into the lipid bilayer membrane of liposomes and wheat germ agglutinin (WGA) was conjugated to the liposomes' surface. Topotecan was then loaded into the above liposomes. In vitro, topotecan liposomes modified with TAM and WGA were applied to the glioma cells, BBB model, and avascular C6 glioma spheroids, respectively. In vivo, they were systemically administered via vein to brain C6 glioma-bearing rats. In view of the microtiter tetrazolium (MTT) results, topotecan liposomes modified with TAM and WGA exhibited a significant inhibitory effect compared to unmodified topotecan liposomes, suggesting that TAM plus WGA contributed strong drug delivery effects into the brain tumor cells after direct drug exposure. In the experiments of drug transport across the BBB model following drug exposure to tumor cells, topotecan liposomes modified with TAM and WGA exhibited the most robust dual-targeting effects: crossing the BBB and then targeting brain tumor cells. Similar strong activity was found in the reduction of C6 glioma tumor spheroid volume and in the apoptosis of the spheroids. In the brain tumor-bearing rats, the dual-targeting effects of topotecan liposomes modified with TAM and WGA could be evidently observed, resulting in a significant improvement in the overall survival of the brain tumor-bearing rats compared with free topotecan and topotecan liposomes. Moreover, results from an extended treatment group indicated that the survival could be further significantly enhanced, indicating that an extended chemotherapy with topotecan liposomes modified with TAM and WGA would be beneficial for treatment. The dual-targeting effects in vivo of topotecan liposomes modified with TAM and WGA could be related to an enhanced effect by TAM via inhibiting efflux of MDR proteins in the BBB and the brain tumor, and an enhanced effect by WGA via endocytosis in the BBB and in the brain tumor. In conclusion, topotecan liposomes modified with TAM and WGA significantly improve topotecan transport across the blood-brain barrier and the survival of brain tumor-bearing animals, showing dual-targeting effects. These findings would encourage further developments of noninvasive therapy for brain tumor.
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PMID:Dual-targeting topotecan liposomes modified with tamoxifen and wheat germ agglutinin significantly improve drug transport across the blood-brain barrier and survival of brain tumor-bearing animals. 1934 15

A series of 7-cycloalkylcamptothecin derivatives were synthesized from camptothecin with two methods. Their biological activities in vitro were evaluated with sulforhodamine-B (SRB) method on four types of human tumor cell lines A549/ATCC, HT29, NCI-H460 and HL60. Most of these camptothecin analogues show higher antitumor activity than the reference compounds SN-38 and Topotecan, with the IC(50) values low to nM level. Structure-activity relationship studies of these compounds mostly match the conclusion we achieved before from quantitative structure-activity relationship (QSAR) research.
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PMID:7-Cycloalkylcamptothecin derivatives: Preparation and biological evaluation. 1954 83

A mathematical model is used to investigate the effectiveness of the chemotherapy drug Topotecan against neuroblastoma. Optimal control theory is applied to minimize the tumor volume and the amount of drug utilized. The model incorporates a state constraint that requires the level of circulating neutrophils (white blood cells that form an integral part of the immune system) to remain above an acceptable value. The treatment schedule is designed to simultaneously satisfy this constraint and achieve the best results in fighting the tumor. Existence and uniqueness of the solution of the optimality system, which is the state system coupled with the adjoint system, is established. Numerical simulations are given to demonstrate the behavior of the tumor and the immune system components represented in the model.
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PMID:Blasting neuroblastoma using optimal control of chemotherapy. 1956 20

The transforming growth factor receptor III (TGFbetaRIII) is the most abundant and essential TGF-beta binding protein that functions as a co-receptor with other receptors in TGF-beta signaling. In earlier studies, expression of TGFbetaRIII was reported to be decreased in a variety of human cancers. Functional assessment of TGFbetaRIII was performed in many previously studied cancers but not in hepatocellular carcinoma. Therefore, in this study, we investigated the expression and genetic alterations of TGFbetaRIII in hepatocellular carcinoma (HCC) by quantitative real-time PCR (qRT-PCR) and single-strand conformation polymorphism (SSCP) analysis. The qRT-PCR showed down-regulation of TGFbetaRIII in the tumor samples. To investigate whether genetic alterations mediated decreased expression of TGFbetaRIII, we performed mutation analysis of 67 human HCC tissues by SSCP and direct sequencing. We found five previously reported and one novel single nucleotide polymorphisms in exons 2, 3, 5, 13 and 14, but no mutations were detected. These polymorphisms were not associated with amino acid changes except for a base change found in exon 2 (TCC-->TTC, S15F). The loss of heterozygosity (LOH) analysis performed on 10 tumors and corresponding normal pairs, showed a low rate of LOH (2/10). The results of this study suggest that TGFbetaRIII is transcriptionally down-regulated in hepatocellular carcinoma. In addition, genetic alterations did not appear to be associated with the reduced expression level of TGFbetaRIII. To clarify the role of TGFbetaRIII in hepatocellular tumor development and progression, functional analysis is needed in future studies.
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PMID:Down-regulation of transforming growth factor beta receptor type III in hepatocellular carcinoma is not directly associated with genetic alterations or loss of heterozygosity. 1963 91


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