Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Camptothecin, a naturally occurring inhibitor of the DNA-replicating enzyme topoisomerase I, demonstrated promising anti-tumor activity in pre-clinical testing; however, because of unexpected toxicity and low anti-tumor effects in the initial clinical trials, further testing was discontinued. We hypothesized that local controlled delivery of camptothecin sodium would achieve effective concentrations in brain tumors without the observed systemic side effects, thereby allowing this novel drug to be used to treat patients with malignant gliomas. To test this hypothesis, we evaluated the sensitivity of rat glioma lines and established human glioma lines to camptothecin in vitro. We found that the LD90 for the established rat and human lines was 0.3 to 1.4 microM after a 1 hr exposure and decreased to less than 0.1 microM after continuous exposure for 7 days. We loaded camptothecin into a controlled-release polymer (ethylene-vinyl acetate co-polymer; EVAc) and showed by high-pressure liquid chromatography that controlled release occurred over at least 21 days. We then tested camptothecin against 9L gliosarcoma, implanted into the brain of Fischer 344 rats. Five days after tumor implantation, animals were treated with camptothecin delivered either systemically or locally by release from EVAc. Local controlled delivery by the polymer significantly extended survival: 59% of the treated animals were long-term survivors (> 120 days) compared to 0% of controls. Systemic administration did not extend survival compared to controls. We compared the efficacy of camptothecin delivered locally with a polymer to camptothecin injected directly into the tumor. Camptothecin increased survival only when delivered locally by polymer.
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PMID:Local delivery of the topoisomerase I inhibitor camptothecin sodium prolongs survival in the rat intracranial 9L gliosarcoma model. 766 33

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

We have isolated a cDNA encoding a rabbit carboxylesterase (CE; EC 3.1.1.1) that converts the camptothecin-derived prodrug irinotecan (CPT-11) to the potent topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin. NH2-terminal amino acid sequencing of a purified rabbit CE allowed the design of redundant oligonucleotides to perform PCR from rabbit liver cDNA. DNA sequencing of the PCR product confirmed the identity of the clone, and after both 5' and 3' rapid amplification of cDNA ends, oligonucleotide primers were designed to amplify the entire cDNA. The 1698-bp open reading frame encoded a 565-amino acid protein containing the characteristic CE B-1 and B-2 motifs, a hydrophobic NH2-terminal leader sequence, and the COOH-terminal residues HIEL that are thought to be responsible for protein localization in the endoplasmic reticulum. Transient expression of the cDNA in COS-7 cells resulted in CE activity in cell extracts and increased the sensitivity of cells to CPT-11. Additionally, stable expression of the rabbit liver CE cDNA in the human glioma U-373 MG cell line resulted in a 56-fold decrease in the IC50 value for CPT-11, whereas the expression of a human alveolar macrophage cDNA encoding a highly homologous CE produced no change in drug sensitivity.
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PMID:Isolation and partial characterization of a cDNA encoding a rabbit liver carboxylesterase that activates the prodrug irinotecan (CPT-11). 963 92

Topotecan is a novel topoisomerase I inhibitor that may have a role in the adjuvant chemotherapy of several solid tumors, including malignant glioma. Here, we have characterized the time- and concentration-dependent toxicity of topotecan in four human malignant glioma cell lines, LN-18, LN-229, LN-308 and T98G. High micromolar concentrations of topotecan, which are unlikely to be achieved in plasma in human patients in vivo, were cytotoxic within 48 hr, induced DNA fragmentation, did not induce major cell cycle changes, failed to consistently alter BCL-2 or BAX protein levels but inhibited RNA synthesis and induced cleavable DNA/topoisomerase I complex formation. Prolonged exposure for 72 hr to high nanomolar to low micromolar concentrations of topotecan augmented p21 protein levels and induced G2/M arrest but failed to consistently alter BCL-2 and BAX protein levels, did not induce significant DNA/topoisomerase I complex formation and did not inhibit RNA synthesis. Neither short-term nor long-term topotecan toxicity was blocked by ectopic expression of bcl-2 or wild-type p53. Transfer of a mutant p53 gene enhanced topotecan sensitivity in wild-type p53 LN-229 but not mutant p53 LN-18 cells. CD95 ligand (CD95L)-induced apoptosis was synergistically enhanced by short-term/high concentration but not long-term/low concentration exposure to topotecan, suggesting that topotecan sensitizes human malignant glioma cells to CD95L-induced apoptosis via inhibition of RNA synthesis. These data suggest that topotecan needs to be administered in high concentrations, such as an intratumoral polymer, to limit glioma cell growth in synergy with CD95L in vivo.
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PMID:Potentiation of CD95L-induced apoptosis of human malignant glioma cells by topotecan involves inhibition of RNA synthesis but not changes in CD95 or CD95L protein expression. 973

To evaluate potential synergistic interactions between topoisomerase I (Topo I) inhibitors, i.e. camptothecin (CPT) and topotecan (TPT), and chemotherapeutic agents known to be active in treatment of brain tumors, in vitro studies were conducted with human glioma and medulloblastoma cell lines. Tumor cells were exposed to CPT or TPT alone or in combination with cisplatin, 4-hydroperoxycyclophosphamide (4-HC), BCNU or etoposide (VP-16). Cytotoxicity was assessed by colony formation assays. Drug interactions were evaluated by means of a novel analytical model which permits statistical evaluation over a range of dose combination. Experimental results were corroborated by published models of drug interaction. Our findings indicate that in vitro cytotoxic interactions in brain tumor cells between Topo I inhibitors and alkylating agents or etoposide depend on drug dose, dose schedule and tumor cell line. Treatment of DAOY medulloblastoma cells with CPT and either cisplatin, 4-HC or VP-16 produced significant synergistic cytotoxicity over a wide range of dose combinations. When VP-16 was administered after CPT, synergy was reduced to a narrow range of dose combinations. For U251 glioma cells, incubation with CPT and cisplatin or 4HC also produced synergistic cytotoxicity over a broad range of dose combinations. By contrast, antagonistic interactions were observed after administration of CPT with BCNU or VP-16. Treatment of U251 cells with CPT and cisplatin produced synergistic or antagonistic cytotoxicity depending on the dose combination used. These findings support a role for pharmacokinetic analysis in multiagent phase 11 trials involving Topo I inhibitors and have important implications for clinical trial design strategies.
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PMID:Synergistic cytotoxicity of topoisomerase I inhibitors with alkylating agents and etoposide in human brain tumor cell lines. 977 9

Deoxyribonucleic acid (DNA) topoisomerases are enzymes which resolve topological problems in eukaryotic DNA, and may be involved in cell proliferation. The involvement of topoisomerase II in cell proliferation was examined in the human glioma cell line T98G. The growth rate of T98G cells was suppressed by treatment with topoisomerase II antisense oligonucleotides dose-dependently, with significant suppression at concentrations greater than of 0.1 mM. The growth rate of T98G treated with control oligonucleotide was suppressed at concentrations greater than 3.0 mM. The activity of topoisomerase II in T98G cells treated with 0.5 mM topoisomerase II antisense oligonucleotide was one fourth of that in cells treated with control oligonucleotide. When topoisomerase II translation was suppressed, the activity of topoisomerase I was increased. These results suggest that de novo synthesis of the topoisomerase II protein is required to maintain a normal growth rate in cultured T98G cells. These topoisomerases may be functionally related, and might provide compensatory mechanisms in the case of compromised function.
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PMID:Inhibition of topoisomerase II alpha subunit de novo synthesis by specific antisense oligonucleotides suppresses human glioma T98G cell growth. 1034 8

In this study, simultaneous administration of certain inhibitors of topoisomerase I and topoisomerase II produced synergistic cytotoxicity in a series of human glioma cell lines. Camptothecin (CPT) and etoposide (VP-16) produced combination indices (CI) <1.0 in all glioma cell lines tested, including those that were relatively resistant to the two topoisomerase inhibitors individually. In contrast, CPT and VP-16 produced additive cytotoxicity in HT-29 and SW-620 colon carcinoma cell lines. To explore the molecular basis for synergy in glioma cells, we focused on one glioma cell line (U87) in which even sub-cytotoxic doses of CPT potentiated the action of VP-16. Except for genistein (a topo II agent with tyrosine kinase inhibitory function), all topo II inhibitors tested (doxorubicin, ellipticine, and m-AMSA) were synergistic with CPT. While CPT and VP-16 produced cytotoxicity and protein-linked DNA breaks (PLDB) that were supra-additive in U87 glioma cells, CPT and genistein produced additive results. Pretreatment of U87 cells with the tyrosine kinase inhibitor tyrphostin-A23 or the tyrosine phosphatase activator O-phospho-L-tyrosine (OPLT) reduced combination PLDB from synergistic to additive levels, but had no effect on the formation of PLDB induced by either CPT or VP-16 alone. CPT and VP-16 also produced a synergistic accumulation of sub-G0 (apoptotic) cells which was blocked by tyrphostin-A23. No significant increase in topoisomerase protein levels could be detected in response to combination treatment. Thus, synergistic effects between topoisomerase I and topoisomerase II inhibitors in U87 glioma cells may depend upon phosphorylation of cellular proteins other than the topoisomerases themselves.
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PMID:Synergistic cytotoxicity, apoptosis and protein-linked DNA breakage by etoposide and camptothecin in human U87 glioma cells: dependence on tyrosine phosphorylation. 1035 42

The accumulation of the topoisomerase I inhibitor topotecan in brain tumor as well as in brain around tumor (BAT) and normal brain following an intravenous bolus of topotecan of 0.5 mg/kg was investigated in rats bearing a 9L glioma. Also the influence of dexamethasone (Dex) on the uptake of topotecan was examined. Tumor, BAT and brain tissue as well as whole blood were collected at 1 h after an i.v. bolus of topotecan. Concentrations of total topotecan in tumor, BAT and brain were quantified with high-performance liquid chromatography (HPLC) and compared with concentrations in plasma of total topotecan. In brain tumor tissue the mean total topotecan concentration was 96 +/- 33 ng/g which was 20-fold higher than the accumulation of topotecan in normal brain tissue. In BAT intermediate concentrations of 13 +/- 4.9 ng/g were reached. Mean total topotecan concentration in plasma was 100 +/- 25 ng/ml. We did not find an influence of Dex on the uptake of topotecan in either tissue. We conclude that high tissue concentrations of topotecan can be reached in experimental brain tumors in rats. This observation may be useful in the design of clinical studies with topotecan.
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PMID:The accumulation of topotecan in 9L glioma and in brain parenchyma with and without dexamethasone administration. 1042 Oct 68

Although topoisomerase inhibitors, such as camptothecin and topotecan, have been widely used in the treatment of nonglial tumors, their application for gliomas has been limited by poor efficacy relative to toxicity that may in part reflect limited bioavailability and blood stability of these agents. However, the potential promise of this class of agents has fostered efforts to develop new, more potent, and less toxic inhibitors that may be clinically relevant. Using a cascade radical annulation route to the camptothecin family, we developed a series of novel camptothecin analogues, 7-silylcamptothecins ("silatecans"), that exhibited potent inhibition of topoisomerase I, dramatically improved blood stability, and sufficient lipophilicity to favor blood-brain barrier transit. We explored the efficacy of a series of these agents against a panel of five high-grade glioma cell lines to identify a promising compound for further preclinical testing. One of the most active agents in our systems (DB67) inhibited tumor growth in vitro with an ED50 ranging between 2 and 40 ng/ml, at least 10-fold more potent than the effects observed with topotecan, and at least comparable with those of SN-38, the active metabolite of CPT-11. Because DB67 also exhibited the highest human blood stability of any of the agents examined, this agent was then selected for in vivo studies. A dose-escalation study of this agent in a nude mouse U87 glioma model system demonstrated a concentration-dependent effect, with tumor growth inhibition at day 28 postimplantation (the day control animals began to require sacrifice because of large tumor size) of 61 +/- 7% and 73 +/- 3% after administration of DB67 doses of 3 and 10 mg/kg/day, respectively, for 5 days beginning on postimplantation day 7. Animals that continued treatment with 10 mg/kg/day in three additional 21-day cycles all remained progression free after >90 days of follow-up but later developed enlarging tumors after treatment was stopped. However, a slightly higher dose (30 mg/kg/day) induced complete tumor regression after only two cycles in all study animals and was effective even if treatment was delayed until large, bulky tumors had developed. Application of the 30 mg/kg/day dose to treat established intracranial glioma xenografts led to long-term (>90 day) survival in six of six animals, whereas all controls died of progressive disease (P < 0.00001). No apparent toxicity was encountered in any of the treated animals. In summary, the present studies indicate that silatecans may hold significant promise for the treatment of high-grade gliomas and provide a rationale for proceeding with further preclinical evaluation of their efficacy and safety versus commercially available camptothecin derivatives.
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PMID:Potent topoisomerase I inhibition by novel silatecans eliminates glioma proliferation in vitro and in vivo. 1051 2

Current systemic treatment options for patients with relapsed gliomas are limited. The topoisomerase I inhibitor topotecan has demonstrated broad antitumor activity in both preclinical studies as well as a number of phase I and II trials in humans. Studies in primates have shown good cerebrospinal fluid levels of topotecan following systemic administration. We therefore performed this phase II trial in patients who developed evidence of progressive glioma after definitive radiation therapy. Patients were treated with 1.5 mg/m2 intravenously daily for 5 consecutive days repeated every three weeks. For patients who had received prior nitrosourea-containing chemotherapy, the starting dose was 1.25 mg/m2. Thirty-three patients were entered on this study. All patients were eligible and evaluable for both response and toxicity. Seven patients experienced grade 4 leukopenia with 2 of these patients dying of infection-related complications. Six of these seven patients were not taking anticonvulsants during treatment. Nine patients developed grade 3-4 thrombocytopenia, seven of whom were not taking anticonvulsants. Nonhematologic side effects were infrequent and manageable. One patient experienced a partial response to this treatment for an overall response rate of 3% (95% binomial confidence interval 0.3%-20.4%). The median time to progression was 14.9 weeks and median survival 19.9 weeks. Topotecan at this dose and schedule showed no substantial activity in relapsed gliomas.
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PMID:A North Central Cancer Treatment Group phase II trial of topotecan in relapsed gliomas. 1095 98


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