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)

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

Irinotecan is a water-soluble derivative of camptothecin, an alkylator originally extracted from the Chinese tree Camptotheca acuminata. Laboratory studies have demonstrated the activity of irinotecan in a broad panel of pediatric and adult central nervous system tumor xenografts in athymic nude mice. These studies led to a Phase II trial that confirmed the activity of this agent in the treatment of recurrent malignant glioma. Subsequent laboratory studies have demonstrated that a combination of irinotecan (CPT-11) and alkylating agents, particularly 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), increases antitumor effects to a level well above the additive effects of the individual agents. These laboratory studies generated a recently completed Phase I trial of CPT-11 + BCNU, which now is being evaluated in a formal Phase II trial for adults with newly diagnosed or recurrent malignant glioma. More recent studies have demonstrated similar interaction between CPT-11 and temozolomide and have led to a Phase I trial of these agents in the treatment of adults with malignant glioma. Studies currently are addressing the role of O(6)-alkylguanine-DNA alkyltransferase (AGT) in reducing the benefits of combining CPT-11 with temozolomide and the potential therapeutic gain from utilizing an inhibitor of AGT.
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PMID:The emerging role of irinotecan (CPT-11) in the treatment of malignant glioma in brain tumors. 1271 57

Patients with malignant glioma continue to have a dismal outcome. Those with glioblastoma multiforme, the most common type of malignant glioma, have a median survival of 40 to 60 weeks following diagnosis and only 16 to 24 weeks after recurrence. While standard therapy is surgery and external-beam radiotherapy, data indicate that chemotherapy improves the clinical outcome of some patients. Irinotecan (CPT-11, Camptosar) possesses significant activity against malignant glioma, and potentiation of this activity with combination partners, including the alkylator 1,2-bis(2-chloroethyl)-1-nitrosourea (carmustine, BCNU), is being evaluated in an ongoing phase II study. Also, the combination of irinotecan plus temozolomide (Temodar) has produced synergism in preclinical studies as well as encouraging responses in ongoing clinical trials. Other investigative directions include studies of irinotecan plus temozolomide and O6-benzylguanine (O6-BG) to assess the ability of O6-BG to maximize the therapeutic benefits of irinotecan combined with temozolomide.
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PMID:Irinotecan: promising activity in the treatment of malignant glioma. 1280 Jun

The primary objective of this study was to determine the proportion of patients exhibiting a radiographic response in a cohort of patients with recurrent malignant glioma who were treated with irinotecan. Secondary objectives were to determine progression-free survival, overall survival, and toxicity. The trial was terminated after the first 18 patients were enrolled in this multicenter, 2-stage, phase 2 study. Twelve patients received concurrent enzyme-inducing antiepileptic drugs, and 6 did not. Each cycle consisted of a 90-min i.v. infusion of irinotecan every week for 4 consecutive weeks, followed by 2 weeks off. One patient had a complete response, 5 patients had stable disease, 5 patients had radiographic progression, 6 patients were removed from the study because of toxicity, and 1 patient refused further therapy and was removed from the study. The response rate in this study was 6% (1/18), and 28% (5/18) of these patients progressed while receiving irinotecan. Dose-limiting toxicities consisted of diarrhea in 5 patients, neutropenia in 1 patient, infection in 1 patient, and respiratory failure in 1 patient. Irinotecan had minimal efficacy in this cohort of 18 patients with recurrent malignant glioma. Toxicity was significant but similar to that reported in other patient populations.
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PMID:Phase 2 study of weekly irinotecan in adults with recurrent malignant glioma: final report of NABTT 97-11. 1476 36

Irinotecan is a topoisomerase I inhibitor previously shown to be active in the treatment of malignant glioma. We now report the results of a phase 1 trial of irinotecan plus BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, for patients with recurrent or progressive MG. Irinotecan dose escalation occurred independently within 2 strata: patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and patients not receiving EIAEDs. BCNU was administered at a dose of 100 mg/m2 over 1 h every 6 weeks on the same day as the first irinotecan dose was administered. Irinotecan was administered intravenously over 90 min once weekly. Treatment cycles consisted of 4 weekly administrations of irinotecan followed by a 2-week rest with dose escalation in cohorts of 3 to 6 patients. Seventy-three patients were treated, including 49 patients who were on EIAEDs and 24 who were not on EIAEDs. The maximum tolerated dose for patients not on EIAEDs was 125 mg/m2. The maximum tolerated dose for patients on EIAEDs was 225 mg/m2. Dose-limiting toxicity was evenly distributed among the following organ systems: pulmonary, gastrointestinal, cardiovascular, neurologic, infectious, and hematologic, without a clear predominance of toxicity involving any one organ system. There was no evidence of increasing incidence of toxicity involving one organ system as irinotecan dose was escalated. On the basis of these results, we conclude that the recommended doses of irinotecan for a phase 2 clinical trial when given in combination with BCNU (100 mg/m2) are 225 mg/m2 for patients on EIAEDs and 125 mg/m2 for patients not on EIAEDs.
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PMID:Phase 1 trial of irinotecan plus BCNU in patients with progressive or recurrent malignant glioma. 1513 29

Treatment of malignant glioma requires a multidisciplinary team. Treatment includes surgery, radiotherapy, and chemotherapy. Recently developed agents have demonstrated activity against recurrent malignant glioma and efficacy if given concurrently with radiotherapy in the upfront setting. Oligodendroglioma with 1p/19q deletions has been recognized as a distinct pathologic entity with particular sensitivity to radiotherapy and chemotherapy. Randomized trials have shown that early neoadjuvant or adjuvant administration of procarbazine, lomustine, and vincristine chemotherapy prolongs disease-free survival; however, it has no impact on overall survival. Temozolomide, a novel alkylating agent, has shown modest activity against recurrent glioma. In combination with radiotherapy in newly diagnosed patients with glioblastoma, temozolomide significantly prolongs survival. Molecular studies have demonstrated that the benefit is mainly observed in patients whose tumors have a methylated methylguanine methyltransferase gene promoter and are thus unable to repair some of the chemotherapy-induced DNA damage. For lower-grade glioma, the use of chemotherapy remains limited to recurrent disease, and first-line administration is the subject of ongoing clinical trials. Irinotecan and agents like gefitinib, erlotinib, and imatinib targeting the epidermal growth factor receptor and platelet-derived growth factor receptor have shown some promise in recurrent malignant glioma. This review summarizes recent developments, focusing on the clinical management of patients in daily neuro-oncology practice.
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PMID:Changing paradigms--an update on the multidisciplinary management of malignant glioma. 1647 37

Malignant glioma is the most commonly occurring primary malignant brain tumor. It is difficult to treat and is usually associated with an inexorable, rapidly fatal clinical course. Chemotherapy, radiotherapy, and surgical excision are core components in the management of malignant glioma. However, chemotherapy, even with the most active regimens currently available, achieves only modest improvement in overall survival. Novel agents and new approaches to therapy are required to improve clinical outcomes. Irinotecan, a first-line treatment for metastatic colorectal cancer and an agent with high activity against solid tumors of the gastrointestinal tract, is an inhibitor of topoisomerase I, a critical enzyme needed for DNA transcription. Irinotecan crosses the blood-brain barrier and, in preclinical investigations, has demonstrated cytotoxic activity against central nervous system tumor xenografts. Its antitumor activity has also been demonstrated against glioblastoma cells with multidrug resistance. Studies in adult and pediatric patients with recurrent, intractable malignant glioma have evaluated irinotecan as monotherapy and in combination with other agents, including temozolomide, carmustine, thalidomide, and bevacizumab. Studies of irinotecan in combination with other medications, particularly temozolomide and bevacizumab, have yielded promising results. Irinotecan monotherapy has demonstrated efficacy; however, its efficacy appears to be enhanced when used in combination with other chemotherapeutic agents. When administered concurrently with enzyme-inducing antiepileptic drugs, the dosage must be increased to compensate for enhanced cytochrome CY3A4/5 enzyme activity. Toxicities associated with irinotecan have been manageable; the most important dose-limiting toxicities are neutropenia and diarrhea. Irinotecan-based chemotherapy of malignant glioma merits further study.
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PMID:Experience with irinotecan for the treatment of malignant glioma. 1878 79

Irinotecan (CPT-11) has shown emerging promise in the treatment of malignant gliomas. It is believed the mechanism of action of irinotecan is to sensitize glioma cells to the cytotoxic action of radiation therapy and alkylating agents. However, clinical trials using weekly or three-weekly doses of CPT-11 have demonstrated imaging responses in only 10-15% of patients. In this study, we evaluated another mechanism of action, angiosuppression by CPT-11 of ACNU-resistant gliomas, using a metronomic administration schedule. Two different types of treatment, (1) conventional and (2) metronomic, were applied to the subcutaneous U87 model. We found that metronomic administration of CPT-11 significantly inhibited malignant glioma growth by inhibiting angiogenesis; this treatment procedure reduced the number of tumor vessels and the area of hypoxic lesions and reduced expression of VEGF and HIF-1alpha, the most important angiogenic factors in gliomas. Metronomic treatment was superior to conventional treatment with regard to the severe systemic side effect of body weight loss. The growth inhibitory effect was very similar for both low and high doses of CPT-11. These angiosuppressive effects of CPT-11 show promise for another use of CPT-11 in metronomic and scheduled angiosuppressive chemotherapy with low dose and long-term administration for malignant gliomas without systemic side effects.
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PMID:Metronomic treatment of malignant glioma xenografts with irinotecan (CPT-11) inhibits angiogenesis and tumor growth. 2006 73

High grade primary CNS gliomas hold some of the worst prognoses of any malignancy, with the vast majority of patients dying within two years of diagnosis, even with aggressive modern treatments. Surgical resection and radiotherapy are cornerstones of treatment when possible. In spite of many years of research, only recently has management with chemotherapy been able to prolong survival in patients with high grade gliomas, albeit only modestly at best. Topoisomerase I (TOP1) inhibitors target an enzyme critical for DNA replication and cell-cycle progression; they cross the blood-brain barrier and have antitumor activity against glioblastoma cells in vitro. The most frequently associated toxicities are neutropenia and diarrhea, but are often manageable. The two most used agents are irinotecan and topotecan. Due to enhanced cytochrome CY3A4/5 enzyme activity, irinotecan dose must be adjusted with concomitant enzyme-inducing antiepileptic drug usage; the data is less clear regarding the effects on topotecan. Clinical trials in patients with recurrent malignant glioma have evaluated TOP1 inhibitors as monotherapy and in combination with other agents. There is evidence for using topotecan with radiotherapy. Irinotecan has limited efficacy as monotherapy, but shows promise in combination with other agents, particularly temozolomide and bevacizumab. Newer generation TOP1 inhibitors are currently being evaluated in phase I trials. TOP1 inhibitors show promising activity in patients with primary CNS malignancies and warrant further study.
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PMID:Topoisomerase I inhibitors in the treatment of primary CNS malignancies: an update on recent trends. 2123 38

Antiangiogenic treatment has recently become an integral part of modern cancer therapy targeting the vasculature of numerous aggressive malignancies including glioblastoma. There is preclinical evidence that antiangiogenic therapies promote glioma cell invasiveness. In clinical series, upon progression on antiangiogenic therapy with the vascular endothelial growth factor-directed antibody bevacizumab (BEV), glioblastoma has been reported to display a more infiltrative pattern of recurrence. This distant spread at recurrence or progression and a gliomatosis cerebri-like growth pattern is best detectable on fluid-attenuated inversion recovery MRI. The frequency of up to 20% to 30% of such a pattern in BEV-treated patients is higher than expected to occur without BEV. Older reports and common clinical knowledge estimate the frequency of diffuse or distant spread in recurrent glioblastoma at 10%. This observation stimulated two streams of research. One is to overcome this often insidious adverse effect of antiangiogenic treatment, to optimize antiangiogenic therapies and to face this major challenge, integrating antiangiogenic with anti-invasive mechanisms into one combined treatment concept. The second is questioning a specific property of antiangiogenic therapy to induce diffuse or distant spread. Here, alternative hypotheses of increased awareness and better imaging as well as invasiveness being part of the natural course of the disease have been tested. Without doubt, migration and invasiveness are major obstacles to successful glioma therapy, notably local therapies, both in the natural course of the disease and in the concept of "evasive resistance." However, clinical analyses of case series, matched pairs analyses, and follow-up on the BRAIN trial (A Study to Evaluate Bevacizumab Alone or in Combination with Irinotecan for Treatment of Glioblastoma Multiforme), which led to accelerated approval of BEV for recurrent glioblastoma in the United States, have not supported a specific propensity of BEV to induce diffuse growth or distant spread at recurrence.
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PMID:Patterns of progression in malignant glioma following anti-VEGF therapy: perceptions and evidence. 2127 15


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