Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topotecan (Hycamtin) is a promising new topoisomerase I-targeting anticancer agent that first entered clinical trials in 1989 under National Cancer Institute sponsorship in collaboration with SmithKline Beecham. In 1996, it was approved for use by the United States Food and Drug Administration (FDA) for previously treated patients with advanced ovarian cancer. For these patients, topotecan provides another therapeutic option upon disease progression after initial platinum-based chemotherapy. Topotecan also has activity in other tumor types, including small-cell lung cancer, hematologic malignancies and pediatric neuroblastoma and rhabdomyosarcoma. Topotecan combination regimens with paclitaxel (Taxol), etoposide (VePesid), cisplatin (Platinol), and cytarabine and with other treatment modalities, such as radiation therapy, are in development. Studies evaluating topotecan combinations as initial treatment in such diseases as ovarian and small-cell lung carcinoma are also underway. It is hoped that earlier use of topotecan, with its novel mechanism of action, will prolong survival and increase cure rates in patients with these chemoresponsive tumors. Whether or not such hopes are realized, these important studies will help define the role of topotecan in cancer chemotherapy.
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PMID:Clinical status and optimal use of topotecan. 939 64

Topotecan (Hycamtin; SmithKline Beecham Pharmaceuticals, Philadelphia, PA), a camptothecin analog, is a novel and specific inhibitor of the nuclear enzyme topoisomerase I. In preclinical studies, topotecan demonstrated significant in vitro activity in a variety of solid tumor explants derived from colorectal, breast, ovarian, renal cell, non-small cell lung cancer, and gastrointestinal sources. Notable activity was also demonstrated in vivo in a wide range of animal tumor models. A large number of phase I studies with topotecan have been conducted since 1992 in both adults and children with a broad range of refractory malignancies and as many as 14 different dosing schedules. Complete, partial, or minor responses were demonstrated in patients with recurrent or refractory neuroblastoma, non-small cell lung cancer, small cell lung cancer, ovarian cancer, breast cancer, colon cancer, esophageal cancer, renal cell carcinoma, and squamous cell carcinoma. The antitumor activity of topotecan in these phase I evaluations was associated more often with frequent or continuous dosing schedules compared with less frequent or short exposure schedules. Maximum tolerated doses were predominantly dependent on the dosing schedule used. Myelosuppression was the major dose-limiting toxicity across all schedules, and nonhematologic toxicities were generally mild. Data from phase I studies have provided valuable information about antitumor responses, maximum tolerated doses, and dose-limiting toxicities associated with different dosing schedules. Based on this information, there was substantial enthusiasm for further evaluating topotecan in a wide range of cancer patients in phase II studies.
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PMID:Review of phase I clinical studies with topotecan. 942 56

DNA-topoisomerase I is the nuclear target of new anticancer drugs, namely camptothecin and its derivatives. In order to establish the rational basis for their clinical development in paediatric oncology, the antitumour activity of irinotecan (CPT-11) and topotecan, two camptothecin water-soluble derivatives, was studied in nude mice bearing neuroblastoma xenografts. The panel was composed of 4 previously established subcutaneous xenograft lines (IGR-N835, IGR-N91, IGR-NB3, IGR-NB8) that exhibited the common biological markers of poor prognosis in children (MYCN amplification, 1p deletion, paradiploidy and/or MDR1 overexpression). Irinotecan and topotecan were administered i.v. or i.p. over 5 consecutive days in animals bearing tumours. Irinotecan (40 mg/kg/day) induced 20-100% complete regressions with tumour growth delays ranging from 20 to 46 days. Two out of 10 IGR-N91 bearing animals were tumour free more than 120 days after treatment with the top dose (50 mg/kg/day). Topotecan (2.7 mg/kg/day) induced 0-67% complete regressions with tumour growth delays ranging from 23 to 50 days. One out of 8 IGR-NB3 bearing mice was tumour free at the end of the experiment. The antitumour activity of both drugs was clearly sustained at a lower dose level. Topoisomerase I activity was assayed in 15 neuroblastomas, 3 ganglioneuroblastomas and 2 normal adrenal glands, using a DNA relaxation assay. Topoisomerase I activity ranged from 69 to 1304 arbitrary units/mg of protein, and was significantly higher in immature neuroblastomas than in ganglioneuroblastomas and adrenal glands. In conclusion, irinotecan and topotecan are active against neuroblastoma xenografts. Their target is expressed in patients' tumour samples. Clinical development of topoisomerase I inhibitors in children with neuroblastoma is warranted.
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PMID:DNA-topoisomerase I, a new target for the treatment of neuroblastoma. 951 44

The antitumor activity of topotecan administered as a 72-h continuous i.v. infusion was evaluated in children with refractory neuroblastoma and sarcomas of soft tissue and bone. We also attempted to increase the dose intensity of topotecan by including an intrapatient dose escalation in the trial design. Ninety-three children (85 eligible and evaluable for response) with recurrent or refractory neuroblastoma, osteosarcoma, Ewing's sarcoma/peripheral neuroectodermal tumor, rhabdomyosarcoma, or other soft-tissue sarcomas received topotecan administered as a 72-h i.v. infusion every 21 days. The initial dose was 1.0 mg/m2/day, with subsequent intrapatient dose escalation to 1.3 mg/m2/day for those patients who did not experience dose-limiting toxicity after their first cycle of topotecan. There was one complete response in a patient with neuroblastoma (n = 26) and one partial response in a patient with Ewing's sarcoma/peripheral neuroectodermal tumor (n = 25). No complete or partial responses were observed in 17 patients with osteosarcoma, 15 patients with rhabdomyosarcoma, or 2 patients with other soft-tissue sarcomas; however, 8 patients had prolonged (15-48 weeks) stable disease while receiving topotecan. Topotecan was well tolerated. The most commonly observed toxicities were myelosuppression (dose-limiting) and nausea and vomiting. Intrapatient dose escalations were performed in 68% of the patients who received more than one cycle of topotecan, and 1.3 mg/m2/day was tolerated by 79% of the patients who received the higher dose and were evaluable for hematological toxicity. In conclusion, topotecan administered as a 72-h continuous infusion every 21 days is inactive (objective response rate, < 20%) in children with refractory or recurrent neuroblastoma and sarcomas of soft tissue or bone.
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PMID:Phase II trial of topotecan administered as 72-hour continuous infusion in children with refractory solid tumors: a collaborative Pediatric Branch, National Cancer Institute, and Children's Cancer Group Study. 951 23

Although the prognosis of childhood cancers has dramatically improved over the last three decades, new active drugs are needed. Camptothecins represent a very attractive new class of anticancer drugs to develop in paediatric oncology. The preclinical and clinical development of two of these DNA-topoisomerase I inhibitors, i.e. topotecan and irinotecan, is ongoing in paediatric malignancies. Here we review the currently available results of this evaluation. Topotecan proved to be active against several paediatric tumour xenografts. In paediatric phase I studies exploring several administration schedules, myelosuppression was dose-limiting. The preliminary results of topotecan evaluation in phase II study showed antitumour activity in neuroblastoma (response rate: 15% at relapse and 37% in newly diagnosed patients with disseminated disease) and in metastatic rhabdomyosarcoma (40% in untreated patients). Topotecan-containing drug combinations are currently investigated. Irinotecan displayed a broad spectrum of activity in paediatric solid tumour xenografts, including rhabdo-myosarcoma, neuroblastoma, peripheral primitive neuroectodermal tumour, medulloblastoma, ependymoma, malignant glioma and juvenile colon cancer. For several of these histology types, tumour-free survivors have been observed among animals bearing an advanced-stage tumour at time of treatment. The clinical evaluation of irinotecan in children is ongoing. Irinotecan undergoes a complex in vivo biotransformation involving several enzyme systems, such as carboxylesterase, UDPGT and cytochrome P450, in children as well as in adults. Preclinical studies of both drugs have shown that their activity was schedule-dependent. The optimal schedule of administration is an issue that needs to be addressed in children. In conclusion, the preliminary results of the paediatric evaluation of camptothecin derivatives show very encouraging results in childhood malignancies. The potential place of camptothecins in the treatment of paediatric malignant tumours is discussed.
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PMID:Preclinical development of camptothecin derivatives and clinical trials in pediatric oncology. 961 66

Topotecan and vincristine were evaluated alone or in combination against 13 independent xenografts and 1 vincristine-resistant derivative, representing childhood neuroblastoma (n = 6), rhabdomyosarcoma (n = 5), or brain tumors (n = 3). Topotecan was given by i.v. bolus on a schedule found previously to be optimal. Drug was administered daily for 5 days on 2 consecutive weeks with cycles repeated every 21 days over a period of 8 weeks. Doses of topotecan ranged from 0.16 to 1.5 mg/kg to simulate clinically achievable topotecan lactone plasma systemic exposures. Vincristine was administered i.v. every 7 days at a fixed dose of 1 mg/kg. Given as a single agent, vincristine induced complete responses (CRs) in all mice bearing two rhabdomyosarcomas (Rh28 and Rh30) and some CRs in Rh12-bearing mice (57%) but relatively few CRs (<29%) in other tumors. As a single agent, topotecan induced CR in a low proportion of tumor lines. A dose-response model with a logit link function was used to investigate whether the combination of topotecan and vincristine resulted in greater than expected responses compared with the activity of the agents when administered alone. Only CR was used to evaluate tumor responses. The combination resulted in significantly greater than expected CRs than individual agents in nine tumor lines (four neuroblastoma, three brain tumors, and two rhabdomyosarcomas). Similar event-free (failure) distributions were shown in SJ-GBM2 glioblastoma xenografts, whether vincristine was administered on day 1 or day 5 of each topotecan course. To determine whether the increased antitumor activity with the combination was attributable to a change in drug disposition, extensive pharmacokinetic studies were performed. However, little or no interaction between these two agents was determined. Toxicity of the combination was marked by prolonged thrombocytopenia and decreased hemoglobin. However, approximately 75 and 80% of the maximum tolerated dose of each single agent, topotecan (1.5 mg/kg) or vincristine (1 mg/kg), could be given in combination, resulting in a combination toxicity index of approximately 1.5. These results show that the therapeutic effect of combining topotecan with vincristine was greater than additive in most tumor models of childhood solid tumors, and toxicity data suggest that this can be administered to mice with only moderate reduction in the dose levels for each agent.
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PMID:Synergy of topotecan in combination with vincristine for treatment of pediatric solid tumor xenografts. 1058 79

Neurotrophins are required for survival of neurons during development and may act as survival factors to cells undergoing stress. We tested whether brain derived neurotrophic factor (BDNF) protects neuroblastoma (NB) cells from cytotoxic agents using a model NB cell line, NB 1643, which expresses functional tropomyosin related kinase B (TRKB) following treatment with all-trans-retinoic acid. TRKB is the receptor for BDNF. BDNF increases the EC50 values in survival assays for cisplatin, doxorubicin, and topotecan by two to three fold. Thus, BDNF does indeed protect cells drugs that damage DNA. Cisplatin and doxorubicin are used to treat NB. Topotecan is in clinical studies for the treatment of NB. Since these drugs induce DNA damage, we also investigated whether BDNF might afford protection from gamma irradiation. BDNF also induces more than a two fold resistance to gamma irradiation. Since BDNF protects cells from agents with different mechanisms of damaging DNA and resistance, it seems likely that BDNF may alter a common signaling pathway required for cell death initiation by DNA damaging agents.
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PMID:Brain derived neurotrophic factor protects human neuroblastoma cells from DNA damaging agents. 1072 7

Topotecan appears to be relatively unaffected by the most common multidrug resistance mechanisms, may potentiate cytotoxicity of alkylators, has good penetration into the central nervous system, is active against a variety of neoplasms, and has myelosuppression as its paramount toxicity. We present our experience with a myeloablative regimen that includes topotecan. Twenty-one patients with poor-prognosis tumors and intact function of key organs received topotecan 2 mg/m2 by 30-min intravenous (i.v.) infusion on days -8, -7, -6, -5, -4; thiotepa 300 mg/m2 by 3 h i.v. infusion on days -8, -7, -6; and carboplatin by 4 h i.v. infusion on days -5, -4, -3 with a daily dose derived from the pediatric Calvert formula, using a targeted area under the curve of seven mg/ml* min ( approximately 500 mg/m2/day). Stem cell rescue was on day 0. The patients were 1 to 29 (median 4) years old; 18 were in complete remission (CR) and three in partial remission (PR). Early toxicities were severe mucositis and erythema with superficial peeling in all patients and a seizure, hypertension, and renal insufficiency followed by veno-occlusive disease in one patient each. Post-transplant treatment included radiotherapy alone (four patients) or plus biological agents (11 patients with neuroblastoma). With a follow-up of 6+ to 32+ (median 11+) months, event-free survivors include 10/11 neuroblastoma patients (first CR), 4/5 brain tumor patients (second PR or CR), 1/3 patients with metastatic Ewing's sarcoma (first or second CR), and a patient transplanted for multiply recurrent immature ovarian teratoma; a patient with desmoplastic small round-cell tumor (second PR) had progressive disease at 8 months. Favorable results for disease control, manageable toxicity, and the antitumor profiles of topotecan, thiotepa, and carboplatin, support use of this three-drug regimen in the treatment of neuroblastoma and brain tumors; applicability to other tumors is still uncertain.
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PMID:Topotecan combined with myeloablative doses of thiotepa and carboplatin for neuroblastoma, brain tumors, and other poor-risk solid tumors in children and young adults. 1160 67

The extent of angiogenesis and/or vascular endothelial growth factor (VEGF) expression in neuroblastoma tumors correlates with metastases, N-myc amplification, and poor clinical outcome. Understanding the mechanisms regulating VEGF expression in neuroblastoma cells provides additional therapeutic options to control neuroblastoma tumor growth. VEGF mRNA is controlled by growth factors and hypoxia via the transcription factor hypoxia-inducible factor (HIF-1alpha). HIF-1alpha protein levels are regulated by the von Hippel Lindau tumor suppressor gene, VHL, which targets HIF-1alpha degradation. To determine whether the levels of VEGF in neuroblastomas are due to mutations in VHL, we evaluated genomic DNA from 15 neuroblastoma cell lines using PCR. We found no mutations in exons 1, 2, or 3 of the VHL gene. VEGF mRNA levels in neuroblastoma cells cultured in serum-free medium increased after 8 to 16 hours in serum, insulin-like growth factor-I (IGF-I), epidermal growth factor, or platelet-derived growth factor. Serum/IGF-I induced increases in HIF-1alpha protein that temporally paralleled increases in VEGF mRNA, whereas HIF-1beta levels were unaffected. VEGF and HIF-1alpha levels were blocked by inhibitors of phosphatidylinositol 3-kinase and mammalian target of rapamycin. Furthermore, we confirmed that HIF-1alpha mediates approximately 40% of the growth factor activity stimulating VEGF protein expression. Topotecan blocked the IGF-I-stimulated increase in HIF-1alpha but not HIF-1beta, and this resulted in a decrease in VEGF in four neuroblastoma cell lines tested. These data indicate that growth factors in an autocrine or paracrine manner play a major role in regulating VEGF levels in neuroblastoma cells and that targeted therapies to phosphatidylinositol 3-kinase, mammalian target of rapamycin, and/or HIF-1alpha have the potential to inhibit VEGF expression and limit neuroblastoma tumor growth.
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PMID:Topotecan blocks hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression induced by insulin-like growth factor-I in neuroblastoma cells. 1593 Feb 97

Neuroblastoma is one of the most common extracranial solid tumours in childhood with a poor prognosis in its advanced stage. Treatment failure is often associated to the occurrence of drug resistance. To date, treatment of paediatric neuroblastoma is still dismal, and therefore novel effective drugs are awaited. In recent years, an increasing interest has concentrated on camptothecin analogues. Topotecan and irinotecan, the only two clinically relevant camptothecin derivatives to date, have entered clinical trials in neuroblastoma but so far the results have been disappointing. Gimatecan (ST1481, LBQ707; 7-t-butoxyiminomethylcamptothecin), is a novel lipophilic camptothecin derivative that was selected from a series of lipophilic analogues rationally designed and synthesized in order to overcome some of the main drawbacks of conventional camptothecins, limiting their clinical efficacy. Gimatecan is endowed with potent antitumour activity, strong topoisomerase I inhibition, stable drug-target interactions and a better pharmacological profile. The present study deals with the comparative evaluation of cellular pharmacology features of gimatecan, topotecan and SN38 in neuroblastoma cell lines. We show that, despite the lowest intracellular accumulation, gimatecan was the most active among the camptothecin analogues studied. Our findings suggest that the high activity of gimatecan in neuroblastoma is related to the ability of this novel analogue to cause a very high number of DNA breaks as assessed by the Comet assay in both cellular or sub-cellular systems. We propose that DNA strand breaks efficiency as measured by the Comet assay might provide important information about the stability of the ternary complexes induced by camptothecin compounds.
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PMID:The novel lipophilic camptothecin analogue gimatecan is very active in vitro in human neuroblastoma: a comparative study with SN38 and topotecan. 1613 2


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