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

The overexpression of the multidrug resistance (mdr1) gene and its product, P-glycoprotein (P-gp), is thought to limit the successful chemotherapy of human tumors. Recent studies demonstrate that SN-38, a metabolite of the camptothecin (CPT) derivative CPT-11, has antitumor effects on several tumors, but the mechanisms responsible for its cytotoxicity remain unclear. We therefore determined whether SN-38 has cytotoxic effects on MDR human glioblastoma GB-1 cells and non-MDR human glioblastoma U87-MG cells. Furthermore, we determined what role SN-38 plays in the induction of cytotoxicity in these tumor cells. In this study, we demonstrated that SN-38 had significantly stronger antitumor effects on GB-1 and U-87MG cells than did CPT (P < 0.01 and P < 0.05, respectively). In addition, findings obtained using a DNA fragmentation assay, Hoechst 33258 staining, in situ end-labeling and cell cycle analysis demonstrated that SN-38 induced apoptosis in these tumors. Our results suggest that SN-38 has a stronger antitumor effect on malignant glioma cells regardless of MDR expression than does CPT, and therefore can be considered a new chemotherapeutic agent potentially effective in the treatment of human primary or recurrent malignant gliomas resistant to chemotherapy.
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PMID:Induction of apoptosis in multi-drug resistant (MDR) human glioblastoma cells by SN-38, a metabolite of the camptothecin derivative CPT-11. 905 55

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

Future success using chemotherapy against human gliomas may result from exploiting unique molecular vulnerabilities of these tumors. Chemotherapy frequently results in DNA damage. When such damage is sensed by the cell, programmed cell death, or apoptosis, may be initiated. However, chemotherapy-induced DNA damage may activate nuclear factor kappa B (NF-kappaB) and block apoptosis. We inhibited NF-kappaB using a gene therapy approach to determine whether this would render human glioma cells more susceptible to chemotherapy. U87 and U251 glioma cell lines were infected with either treatment adenovirus containing the gene for a mutant non-degradable form of IkappaBalpha, which is an inhibitor of NF-kappaB nuclear translocation, or empty control virus. Following viral infection, cells were treated either with BCNU, carboplatin, tumor necrosis factor alpha (TNF-alpha), or SN-38. Chemotherapy resulted in a marked increase in active intranuclear NF-kappaB. This response was greatly decreased by insertion of the mutant repressor gene. Similarly, a significant increase in cell killing by all chemotherapy age was demonstrated following infection with treatment virus. Expression of the mutant repressor gene also resulted in increased apoptosis by TUNEL assay following chemotherapy. Numerous genes are responsible for glioma chemoresistance. DNA damage by chemotherapy may induce the antiapoptotic factor NF-kappaB and prevent programmed cell death. Insertion of a mutant inhibitor of NF-kappaB strips cells of this antiapoptotic defense and renders them more susceptible to killing by chemotherapy via increased apoptosis.
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PMID:Potentiation of chemotherapeutic agents following antagonism of nuclear factor kappa B in human gliomas. 1267 10

Other than nitrosoureas (carmustine and lomustine) and temozolomide, no agents have consistently demonstrated clinically meaningful benefits for patients with gliomas. The active metabolite of irinotecan, 7-ethyl-10-hydroxy camptothecin (SN-38), exhibited promising antitumor effects in preclinical glioma models. Clinical trials using weekly or every 3 weeks dosing of irinotecan have been completed. Toxicity consisted primarily of mild to moderate neutropenia and diarrhea with both schedules, with occasional severe toxicity including one death from neutropenia and infection. Preliminary analyses have suggested imaging responses in 10-15% of patients. Preclinical models and our understanding of the mechanism of action suggest that irinotecan may sensitize glioma cells to the cytotoxic actions of radiation therapy and alkylating agents; clinical trials designed to assess the therapeutic benefit of combination therapy currently are in progress. There is substantial clinical evidence that the concurrent administration of irinotecan with certain anticonvulsants produces reduced exposure to SN-38. In the absence of anticonvulsants, there is also substantial interpatient variability in drug exposure, perhaps reflecting inherited differences in drug metabolism. Finally several mechanisms of tumor cell resistance to irinotecan have been hypothesized, but the clinical significance of these observations has not been confirmed. Correlative studies to address these pharmacokinetic, pharmacogenetic, and drug resistance questions are ongoing.
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PMID:Irinotecan in the treatment of glioma patients: current and future studies of the North Central Cancer Treatment Group. 1271 56

The topoisomerase-I inhibitor irinotecan (CPT-11) is currently used in Phase I/II trials for the treatment of patients with recurrent malignant gliomas. Protein kinase C (PKC) inhibitors such as high-dose tamoxifen and hypericin also have been used in the treatment of malignant gliomas. The current study examined the role of PKC inhibitors as chemosensitizers for CPT-11 and their proposed mechanism of action. Two glioma cell lines (A-172 and U-87) and one primary glioma cell culture (LA-567) were used. Proliferation ((3)H-thymidine) and cytotoxicity (methylthiotetrazole) studies were performed using CPT-11 (0-100 microM) alone, 7-ethyl-10-hydroxy camptothecin (SN-38) (0-1000 nM) alone or in the presence of a PKC inhibitor, tamoxifen (10 microM), hypericin (10 microM), calphositin C (400 nM), or staurosporine (10 nM). The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL) assay was used to determine apoptosis as the mechanism of cytotoxicity; alterations in bcl-2 and bax expression were determined using Western blot analysis. Conversion of CPT-11 to SN-38 by glioma cells was determined using high-performance liquid chromatography (HPLC) analysis. Increasing CPT-11 and SN-38 concentrations induced cytotoxic morphologic changes, decreased proliferation, and increased cytotoxicity on all glioma cell lines tested. These changes were increased in the presence of a PKC inhibitor. The mechanism of the cytotoxicity was determined to be apoptosis by the TUNEL assay. The combination of a PKC inhibitor with CPT-11 or SN-38 led to decreased expression of the antiapoptotic protein bcl-2, and increased expression of the proapoptotic protein bax. HPLC analysis demonstrated conversion of CPT-11 to SN-38 by glioma cells. A combination of CPT-11 or SN-38 with a PKC inhibitor was found to lead to a decrease in proliferation and an increase in apoptosis in malignant glioma cells. The induction of apoptosis was secondary to a decrease in bcl-2 and an increase in bax expression. Glioma cells are capable of converting CPT-11 to SN-38 by intrinsic tumor carboxylesterases.
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PMID:Combination therapy with irinotecan and protein kinase C inhibitors in malignant glioma. 1271 58

The authors set out to determine the effect of intrapatient dose escalation of irinotecan on its disposition in pediatric patients with high-grade glioma who received concomitant enzyme-inducing anticonvulsants (EIAs). During Course 1, a 60-minute intravenous infusion of irinotecan (20 mg/m(2) per day) was administered once daily for 5 days on each of 2 consecutive weeks. The authors measured the concentrations of the lactone forms of irinotecan and its metabolites 7-ethyl-10-hydroxycamptothecin (SN-38), SN-38 glucuronide, and 7-ethyl-10-[4-N-(5-aminopeptanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC) in serial plasma samples collected on Days 1 and 12 of Course 1. For the 6 patients who received EIAs but whose SN-38 areas under the concentration-time curve (AUCs) on Day 1 were below clinically significant levels, irinotecan dosage was increased, and subsequent pharmacokinetic studies were performed. Thirty-five patients were enrolled. The rate of irinotecan clearance was greater for patients who received EIAs than for those who did not (P = 0.0008), whereas systemic exposure to irinotecan (P = 0.02) and SN-38 (P = 0.0001) was lower for those treated with EIAs than for those who were not. Of the 6 patients whose irinotecan dosages were increased, 3 experienced an increase in the SN-38 AUC between Days 1 and 12. For 1 patient, the SN-38 AUC on Day 12 was lower than on Day 1; this result likely was due to an increased dose of EIAs during the same period. Despite irinotecan dose escalation to 60 and 80 mg/m(2), the SN-38 AUCs for 2 patients did not increase to clinically significant levels. The type and grade of toxicity did not differ between the two patient groups. Increasing the dosage of irinotecan increased the SN-38 AUC in some patients who received concomitant EIA therapy.
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PMID:Effect of intrapatient dosage escalation of irinotecan on its pharmacokinetics in pediatric patients who have high-grade gliomas and receive enzyme-inducing anticonvulsant therapy. 1271 59

Two studies were performed to evaluate the safety, tolerability, and efficacy of irinotecan (CPT-11) in the treatment of adults with malignant glioma. Patients with progressive or recurrent malignant gliomas were enrolled. In the first study, CPT-11 was administered once every 3 weeks as a 90-minute intravenous infusion at a dose of 300 mg/m(2). After 2 treatments, doses were increased to 350 mg/m(2) in those patients without Grade 3/4 toxicities. Dose modifications were made for toxicities. All 14 patients who enrolled (11 males and 3 females) were treated with CPT-11 and were assessable for survival, response, and toxicity. The majority of patients (86%) had prior surgery. Two patients had a confirmed partial response (PR), and 2 patients (14%) had stable disease (SD). Median survival was 24 weeks; median time to tumor progression (TTP) was 6 weeks. The primary hematologic toxicity was Grade 3/4 neutropenia, which was observed in 14% of patients. Infrequent Grade 3/4 nonhematologic toxicity was observed, possibly due to the concomitant use of anticonvulsants that might have altered pharmacokinetics. The second study evaluated the potential underdosing observed in patients who did or did not receive enzyme-inducing antiepileptic drugs (EIAED) by implementing an intrapatient dose escalation design. In this open-label study, treatment of patients with recurrent malignant glioma (rMG) was started at 300-400 mg/m(2) of CPT-11 every 3 weeks and, depending on individual safety and efficacy evaluation, escalated by steps of 100 mg/m(2) in subsequent courses. Thirty-five patients (median age, 43 years; gender, 11F and 24M; histology, 26 glioblastoma multiforme and 9 anaplastic glioma) have completed at least two cycles of chemotherapy and are evaluable for toxicity and response. Dose-limiting toxicity (DLT) was reached in 12 patients at doses ranging from 400-1700 mg/m(2). Preliminary efficacy data show that 3 patients exhibited PR and 15 patients exhibited SD. Median TTP was 2.7 months, and median survival was 8.5 months. Patients who did not receive anticonvulsants achieved higher peak concentrations, relative to dose, of the active metabolite SN-38 than did patients in the EIAED group. This study confirmed the activity of CPT-11 in malignant glioma and indicated that the maximum tolerated dose (MTD) for patients with rMG was considerably higher than expected but still possessed significant variability. A higher level of efficacy for CPT-11 may be observed if an MTD can efficiently be established for each patient.
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PMID:Two studies evaluating irinotecan treatment for recurrent malignant glioma using an every-3-week regimen. 1271 60

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (irinotecan, CPT-11) is a camptothecin prodrug that is metabolized by carboxylesterases (CE) to the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), a topoisomerase I inhibitor. CPT-11 has shown encouraging antitumor activity against a broad spectrum of tumor types in early clinical trials, but hematopoietic and gastrointestinal toxicity limit its administration. To increase the therapeutic index of CPT-11 and to develop other prodrug analogues for enzyme/prodrug gene therapy applications, our laboratories propose to develop camptothecin prodrugs that will be activated by specific CEs. Specific analogues might then be predicted to be activated, for example, predominantly by human liver CE(hCE1), by human intestinal CE (hiCE), or in gene therapy approaches using a rabbit liver CE (rCE). This study describes a molecular modeling approach to relate the structure of rCE-activated camptothecin prodrugs with their biological activation. Comparative molecular field analysis, comparative molecular similarity index analysis, and docking studies were used to predict the biological activity of a 4-benzylpiperazine derivative of CPT-11 [7-ethyl-10-[4-(1-benzyl)-1-piperazino]carbonyloxycamptothecin (BP-CPT)] in U373MG glioma cell lines transfected with plasmids encoding rCE or hiCE. BP-CPT has been reported to be activated more efficiently than CPT-11 by a rat serum esterase activity; however, three-dimensional quantitative structure-activity relationship studies predicted that rCE would activate BP-CPT less efficiently than CPT-11. This was confirmed by both growth inhibition experiments and kinetic studies. The method is being used to design camptothecin prodrugs predicted to be activated by specific CEs.
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PMID:Activation of a camptothecin prodrug by specific carboxylesterases as predicted by quantitative structure-activity relationship and molecular docking studies. 1461 91

This study was conducted to determine the maximum tolerated dose and dose-limiting toxicity of irinotecan (CPT-11) administered every 3 weeks to adults with progressive malignant glioma who were treated with enzyme inducing antiepileptic drug (EIAED) therapy, and to compare the pharmacokinetics with those in patients not on EIAED therapy treated at the recommended phase 2 dose for other cancers. The CPT-11 dose was 350 mg/m(2) i.v. every 3 weeks and remained fixed in patients not on EIAED therapy, but the dose was escalated by 50-mg/m(2) increments in patients on EIAED therapy. CPT-11 and its metabolites SN-38, SN-38 glucuronide (SN-38G), and APC (7-ethyl-10[4-N-(5 aminopentanoic acid)-1-piperidine]-carbonyloxycamptothecin) were characterized in both groups. Patients on EIAEDs received 350 to 800 mg/m(2) of CPT-11. Dose-limiting toxicity was due to grade 3 diarrhea despite maximal doses of loperamide. The systemic levels of CPT-11, APC, SN-38G, and SN-38 were all lower in the EIAED group. There was a moderate-to-fair relationship between CPT-11 dose and the area under the curve (AUC) for CPT-11 and APC over the 2, but no relationship dosage range of 350 to 800 mg/m between CPT-11 dose and the AUC for SN-38 or SN-38G. At the 750-mg/m(2) dose, the AUC for CPT-11 (21.6 microg x h/ml) matched the AUC (21.6 microg x h/ml) in the non-EIAED group treated with 350 mg/m(2) of CPT-11. We conclude that the recommended phase 2 dose of CPT-11 for patients on EIAEDs is 750 mg/m(2) when given every 3 weeks. A phase 2 study of patients with recurrent malignant glioma is ongoing to assess the efficacy of CPT-11 when the dose is stratified according to the use of EIAEDs.
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PMID:Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American Brain Tumor Consortium study. 1476 40

Recent published reports on clinical trials of CPT-11 indicate the effectiveness of this compound, a prodrug of SN-38, against malignant glioma in combination with anti-vascular endothelial growth factor antibody. Here, we determined if NK012, and SN-38 incorporating micelle, can be an appropriate formulation for glioblastoma treatment compared with CPT-11. In vitro cytotoxicity was evaluated against several glioma lines with NK012, CPT-11, SN-38, ACNU, CDDP and etoposide. For the in vivo test, a human glioma line (U87MG) transfected with the luciferase gene was inoculated into nude mice brain for pharmacokinetic analysis by fluorescence microscopy and high-performance liquid chromatography after intravenous injection of NK012 and CPT-11. In vivo antitumor activity of NK012 and CPT-11 was evaluated by bioluminescence image and Kaplan-Meier analyses. The growth-inhibitory effects of NK012 were 34- to 444-fold more potent than those of CPT-11. Markedly enhanced and prolonged distribution of free SN-38 in the xenografts was observed after NK012 injection compared with CPT-11. NK012 showed significantly potent antitumor activity against an orthotopic glioblastoma multiforme xenograft and significantly longer survival rate than CPT-11 (p = 0.0014). This implies that NK012 can pass through the blood brain tumor barrier effectively. NK012, which combines enhanced distribution with prolonged sustained release, may be ideal for glioma treatment. Currently, a phase I study of NK012 is almost complete in Japan and the US. The present translational study warrants the clinical phase II study of NK012 in patients with malignant glioma.
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PMID:Potent antitumor effect of SN-38-incorporating polymeric micelle, NK012, against malignant glioma. 1918 1


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