pyrimidinones and Glioma

pyrimidinones has been researched along with Glioma* in 33 studies

Trials

4 trial(s) available for pyrimidinones and Glioma

ArticleYear
Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial.
    Nature medicine, 2023, Volume: 29, Issue:5

    BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110 .

    Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Glioma; Humans; Imidazoles; Mutation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2023
Dabrafenib plus trametinib in patients with BRAF
    The Lancet. Oncology, 2022, Volume: 23, Issue:1

    Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAF. This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and academic cancer centres in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients with BRAF. Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis 16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-up was 12·7 months (IQR 5·4-32·3) and 15 (33%; 95% CI 20-49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses. In the low-grade glioma cohort, median follow-up was 32·2 months (IQR 25·1-47·8). Nine (69%; 95% CI 39-91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses. Grade 3 or worse adverse events were reported in 31 (53%) patients, the most common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%]).. Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAF. Novartis.

    Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Female; Glioma; Humans; Imidazoles; Isocitrate Dehydrogenase; Male; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Young Adult

2022
A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01.
    BMC cancer, 2019, Dec-27, Volume: 19, Issue:1

    Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study.. The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment.. Trametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN.. ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.

    Topics: Adolescent; Antineoplastic Agents; Canada; Child; Child, Preschool; Glioma; Humans; Infant; MAP Kinase Signaling System; Neurofibroma, Plexiform; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Treatment Outcome; Young Adult

2019
Phase II trial of ritonavir/lopinavir in patients with progressive or recurrent high-grade gliomas.
    Journal of neuro-oncology, 2011, Volume: 102, Issue:2

    Current therapies for recurrent or progressive high-grade gliomas (HGG, WHO grade 3-4) produce a 6-month progression-free survival of only 10-25%. Migration and invasion by HGG is mediated in part by matrix metalloproteases (MMPs) which promote remodeling of the extracellular matrix. Several HIV protease inhibitors (HIVPI) decrease the expression of MMPs in astrocytes and microglia. Given these mechanisms of antitumor activity of HIVPI, we evaluated the efficacy of ritonavir/lopinavir, a combination HIVPI, in patients with progressive or recurrent HGG in an open label phase II trial. Nineteen patients were treated in this study. Patients received ritonavir/lopinavir (400 mg/100 mg) orally twice daily. All patients were treated until progression of disease or unacceptable toxicity. A complete response was seen in one patient (5%). Three patients (16%) had stable disease as the best response. Fifteen patients (79%) had progressive disease. The 6-month progression free survival (PFS(6)) was 11% (2 of 19 patients). Ritonavir/lopinavir was well tolerated in patients with heavily pretreated refractory HGG, and no grade 3 or 4 toxicity was seen. The activity at the dose and schedule used in this study, however, was modest and the study did not meet its efficacy endpoint.

    Topics: Adult; Aged; Brain Neoplasms; Disease Progression; Drug Therapy, Combination; Female; Glioma; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Neoplasm Recurrence, Local; Pyrimidinones; Ritonavir; Survival Rate; Treatment Outcome

2011

Other Studies

29 other study(ies) available for pyrimidinones and Glioma

ArticleYear
Targeted Therapy Win in BRAF-Mutant Gliomas.
    Cancer discovery, 2023, 11-01, Volume: 13, Issue:11

    Two reports from the phase II TADPOLE trial show the benefit of molecularly targeted therapy in pediatric brain tumors with BRAF mutations. Dabrafenib combined with trametinib was superior to chemotherapy in low-grade gliomas and yielded favorable responses in a single-arm study of high-grade ones, results that highlight the importance of biomarker testing in pediatric glioma care.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Child; Glioma; Humans; Mutation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2023
Regulation of TORC1 by MAPK Signaling Determines Sensitivity and Acquired Resistance to Trametinib in Pediatric BRAFV600E Brain Tumor Models.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2022, 09-01, Volume: 28, Issue:17

    We investigated why three patient-derived xenograft (PDX) childhood BRAFV600E-mutant brain tumor models are highly sensitive to trametinib. Mechanisms of acquired resistance selected in situ, and approaches to prevent resistance were also examined, which may translate to both low-grade glioma (LGG) molecular subtypes.. Sensitivity to trametinib [MEK inhibitor (MEKi)] alone or in combination with rapamycin (TORC1 inhibitor), was evaluated in pediatric PDX models. The effect of combined treatment of trametinib with rapamycin on development of trametinib resistance in vivo was examined. PDX tissue and tumor cells from trametinib-resistant xenografts were characterized.. In pediatric models TORC1 is activated through ERK-mediated inactivation of the tuberous sclerosis complex (TSC): consequently inhibition of MEK also suppressed TORC1 signaling. Trametinib-induced tumor regression correlated with dual inhibition of MAPK/TORC1 signaling, and decoupling TORC1 regulation from BRAF/MAPK control conferred trametinib resistance. In mice, acquired resistance to trametinib developed within three cycles of therapy in all three PDX models. Resistance to trametinib developed in situ is tumor-cell-intrinsic and the mechanism was tumor line specific. Rapamycin retarded or blocked development of resistance.. In these three pediatric BRAF-mutant brain tumors, TORC1 signaling is controlled by the MAPK cascade. Trametinib suppressed both MAPK/TORC1 pathways leading to tumor regression. While low-dose intermittent rapamycin to enhance inhibition of TORC1 only modestly enhanced the antitumor activity of trametinib, it prevented or retarded development of trametinib resistance, suggesting future therapeutic approaches using rapamycin analogs in combination with MEKis that may be therapeutically beneficial in both KIAA1549::BRAF- and BRAFV600E-driven gliomas.

    Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Disease Models, Animal; Glioma; Humans; Mechanistic Target of Rapamycin Complex 1; Mice; Mitogen-Activated Protein Kinase Kinases; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sirolimus

2022
Trametinib-associated Hyponatremia in a Child With Low-grade Glioma is Not Seen Following Treatment With Alternative MEK Inhibitor.
    Journal of pediatric hematology/oncology, 2021, 05-01, Volume: 43, Issue:4

    Molecularly targeted therapy with MEK inhibitors has been increasingly incorporated into the treatment of pediatric low-grade gliomas, but this promising therapy is associated with distinctive and specific toxicities. Understanding life-threatening MEK inhibitor toxicities and their management is critical to MEK inhibitor safety, especially among young children. This report describes severe hyponatremia associated with trametinib in an infant with progressive low-grade glioma without underlying endocrine dysfunction, which recurred despite significant dose reduction. Therapy with an alternative MEK inhibitor, binimetinib, provided excellent tumor response without hyponatremia, suggesting that some toxicities may be avoided by changing MEK inhibitor agents within the same class.

    Topics: Antineoplastic Agents; Benzimidazoles; Glioma; Humans; Hyponatremia; Infant; Male; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

2021
Re-irradiation with concurrent BRAF and MEK inhibitor therapy.
    Pediatric blood & cancer, 2021, Volume: 68, Issue:5

    Topics: Adolescent; Brain Neoplasms; Chemoradiotherapy; Fatal Outcome; Glioma; Humans; Imidazoles; Male; MAP Kinase Kinase Kinases; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Re-Irradiation

2021
Trametinib therapy for children with neurofibromatosis type 1 and life-threatening plexiform neurofibroma or treatment-refractory low-grade glioma.
    Cancer medicine, 2021, Volume: 10, Issue:11

    To describe a series of children with extensive PNF or treatment refractory PLGG treated on a compassionate basis with trametinib.. We report on six patients with NF-1 treated with trametinib on a compassionate basis at British Columbia Children's Hospital since 2017. Data were collected retrospectively from the patient record. RAPNO and volumetric criteria were used to evaluate the response of intracranial and extracranial lesions, respectively.. Subjects were 21 months to 14 years old at the time of initiation of trametinib therapy and 3/6 subjects are male. Duration of therapy was 4-28 months at the time of this report. All patients had partial response or were stable on analysis. Two patients with life-threatening PNF had a partial radiographic response in tandem with significant clinical improvement and developmental catch up. One subject discontinued therapy after 6 months due to paronychia and inadequate response. The most common adverse effect (AE) was grade 1-2 paronychia or dermatitis in 5/6 patients. There were no grade 3 or 4 AEs. At the time of this report, five patients remain on therapy.. Trametinib is an effective therapy for advanced PNF and refractory PLGG in patients with NF-1 and is well tolerated in children. Further data and clinical trials are required to assess tolerance, efficacy and durability of response, and length of treatment required in such patients.

    Topics: Adolescent; Antineoplastic Agents; Brain Neoplasms; British Columbia; Child; Child, Preschool; Compassionate Use Trials; Dermatitis, Atopic; Drug Resistance, Neoplasm; Female; Glioma; Humans; Infant; Male; Neurofibroma, Plexiform; Neurofibromatosis 1; Paronychia; Pyridones; Pyrimidinones; Retrospective Studies; Treatment Outcome

2021
Unbiased Proteomic and Phosphoproteomic Analysis Identifies Response Signatures and Novel Susceptibilities After Combined MEK and mTOR Inhibition in BRAF
    Molecular & cellular proteomics : MCP, 2021, Volume: 20

    The mitogen-activated protein kinase pathway is one of the most frequently altered pathways in cancer. It is involved in the control of cell proliferation, invasion, and metabolism, and can cause resistance to therapy. A number of aggressive malignancies, including melanoma, colon cancer, and glioma, are driven by a constitutively activating missense mutation (V600E) in the v-Raf murine sarcoma viral oncogene homolog B (BRAF) component of the pathway. Mitogen-activated protein kinase kinase (MEK) inhibition is initially effective in targeting these cancers, but reflexive activation of mammalian target of rapamycin (mTOR) signaling contributes to frequent therapy resistance. We have previously demonstrated that combination treatment with the MEK inhibitor trametinib and the dual mammalian target of rapamycin complex 1/2 inhibitor TAK228 improves survival and decreases vascularization in a BRAF

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzoxazoles; Brain Neoplasms; Cell Line, Tumor; Female; Glioma; Humans; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Phosphoproteins; Protein Kinase Inhibitors; Proteomics; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidines; Pyrimidinones; TOR Serine-Threonine Kinases

2021
Pneumocephalus in a Pediatric Patient with Glioma Receiving Trametinib.
    Pediatric neurosurgery, 2020, Volume: 55, Issue:1

    The mitogen-activated protein kinase (MAPK) pathway consists of the Ras/Raf/MEK/ERK signaling cascade, and its upregulation plays a major role in the pathogenesis of pediatric astrocytomas and molecular inhibitors of this pathway including trametinib and dabrafenib have been tested in early-phase clinical trials and used by pediatric oncologists in children with BRAF-mutated gliomas. We report a clinical case where a child with progressive BRAF-mutated glioma developed an uncommon and difficult to manage complication - pneumocephalus from intracranial air entry and trapping through dehisced surgical wounds and preexisting skull burr holes. The patient's wound breakdown coincided with skin toxicity from MEK inhibitor therapy. With increasing use of targeted molecular inhibitors in pediatric neuro-oncology, this case illustrates the potentially complicated course of MEK inhibitor therapy in patients with scalp surgical wounds and burr holes that were placed within few weeks from initiation of drug therapy, especially if patients have additional factors that can contribute to poor wound healing such as use of steroids and malnutrition.

    Topics: Child, Preschool; Female; Glioma; Humans; MAP Kinase Signaling System; Pneumocephalus; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Surgical Wound Dehiscence

2020
Recalcitrant trametinib-induced paronychia treated successfully with topical timolol in a pediatric patient.
    Dermatologic therapy, 2020, Volume: 33, Issue:1

    Paronychia has been described as a side effect in patients undergoing treatment with MEK (mitogen activated protein kinase enzyme) inhibitors. It is usually a recurrent condition that can have a significant impact in the quality of life. Topical beta blocker treatment has been described as an effective therapy in antineoplastic-induced pyogenic granulomas and in antineoplastic-induced paronychia. We describe the first case treated with topical timolol for a trametinib-induced paronychia in a pediatric patient that allowed to continue the third line antineoplastic therapy for his glioma.

    Topics: Administration, Topical; Adrenergic beta-Antagonists; Antineoplastic Agents; Child, Preschool; Glioma; Humans; Male; Paronychia; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Timolol; Treatment Outcome

2020
Trametinib for the treatment of recurrent/progressive pediatric low-grade glioma.
    Journal of neuro-oncology, 2020, Volume: 149, Issue:2

    Pediatric low-grade gliomas (pLGGs) are the most common CNS tumor of childhood and comprise a heterogenous group of tumors. Children with progressive pLGG often require numerous treatment modalities including surgery, chemotherapy, rarely radiation therapy and, more recently, molecularly targeted therapy. We describe our institutional experience using the MEK inhibitor, trametinib, for recurrent/progressive pLGGs.. We performed a retrospective, IRB-approved, chart review of all pediatric patients treated with trametinib for recurrent/progressive pLGGs at Dana-Farber/Boston Children's Cancer and Blood Disorder Center between 2016 and 2018.. Eleven patients were identified, of which 10 were evaluable for response. Median age at commencement of trametinib treatment was 14.7 years (range 7.3-25.9 years). Tumor molecular status included KIAA1549-BRAF fusion (n = 4), NF1 mutation (n = 4), FGFR mutation (n = 1) and CDKN2A loss (n = 1). Median number of prior treatment regimens was 5 (range 1-12). Median duration of treatment with trametinib was 19.2 months (range 3.8-29.8 months). Based on modified RANO criteria, best responses included partial (n = 2), minor response (n = 2) and stable disease (n = 6). Two patients remain on therapy (29.8 and 25.9 months, respectively). The most common toxicities attributable to trametinib were rash, fatigue and gastrointestinal disturbance. Five patients required dose reduction for toxicities. Two patients experienced significant intracranial hemorrhage (ICH) while on trametinib. While it is unclear whether ICH was directly attributable to trametinib, therapy was discontinued.. Trametinib appears to be an effective treatment for patients with recurrent/progressive pLGG. The toxicities of this therapy warrant further investigation, with particular attention to the potential risk for intracranial hemorrhage. Early phase multi-institutional clinical trials are underway.

    Topics: Adolescent; Adult; Antineoplastic Agents; Brain Neoplasms; Child; Female; Follow-Up Studies; Glioma; Humans; Male; Neoplasm Recurrence, Local; Prognosis; Pyridones; Pyrimidinones; Retrospective Studies; Young Adult

2020
Combined treatment with CBP and BET inhibitors reverses inadvertent activation of detrimental super enhancer programs in DIPG cells.
    Cell death & disease, 2020, 08-21, Volume: 11, Issue:8

    Diffuse intrinsic pontine gliomas (DIPG) are the most aggressive brain tumors in children with 5-year survival rates of only 2%. About 85% of all DIPG are characterized by a lysine-to-methionine substitution in histone 3, which leads to global H3K27 hypomethylation accompanied by H3K27 hyperacetylation. Hyperacetylation in DIPG favors the action of the Bromodomain and Extra-Terminal (BET) protein BRD4, and leads to the reprogramming of the enhancer landscape contributing to the activation of DIPG super enhancer-driven oncogenes. The activity of the acetyltransferase CREB-binding protein (CBP) is enhanced by BRD4 and associated with acetylation of nucleosomes at super enhancers (SE). In addition, CBP contributes to transcriptional activation through its function as a scaffold and protein bridge. Monotherapy with either a CBP (ICG-001) or BET inhibitor (JQ1) led to the reduction of tumor-related characteristics. Interestingly, combined treatment induced strong cytotoxic effects in H3.3K27M-mutated DIPG cell lines. RNA sequencing and chromatin immunoprecipitation revealed that these effects were caused by the inactivation of DIPG SE-controlled tumor-related genes. However, single treatment with ICG-001 or JQ1, respectively, led to activation of a subgroup of detrimental super enhancers. Combinatorial treatment reversed the inadvertent activation of these super enhancers and rescued the effect of ICG-001 and JQ1 single treatment on enhancer-driven oncogenes in H3K27M-mutated DIPG, but not in H3 wild-type pedHGG cells. In conclusion, combinatorial treatment with CBP and BET inhibitors is highly efficient in H3K27M-mutant DIPG due to reversal of inadvertent activation of detrimental SE programs in comparison with monotherapy.

    Topics: Acetylation; Astrocytoma; Azepines; Brain Stem Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; CREB-Binding Protein; Diffuse Intrinsic Pontine Glioma; Gene Expression Regulation, Neoplastic; Glioma; Histones; Humans; Mutation; Nuclear Proteins; Nucleosomes; Proteins; Pyrimidinones; Transcription Factors; Transcriptional Activation; Triazoles

2020
Neuropsychological impact of trametinib in pediatric low-grade glioma: A case series.
    Pediatric blood & cancer, 2020, Volume: 67, Issue:12

    Clinical trials of MEK inhibitors are underway in pediatric low-grade glioma (PLGG) with BRAF oncogene mutations and recurrent/refractory disease. Cognitive and behavioral impacts of MEK inhibitors, such as trametinib, are unknown as these outcomes have not yet been studied. This case series compared cognition and behavior in eight PLGG cases prior to and while on treatment with trametinib compared to four PLGG controls. Intelligence in the trametinib cases was mainly unchanged while on treatment, with mild decline in one of seven cases with complete data. Parent-reported depression symptoms increased in five of eight trametinib cases relative to one of four controls.

    Topics: Antineoplastic Agents; Brain Neoplasms; Child; Child, Preschool; Cognitive Dysfunction; Depression; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Glioma; Humans; Infant; Male; Neuropsychological Tests; Prognosis; Pyridones; Pyrimidinones

2020
Response to trametinib treatment in progressive pediatric low-grade glioma patients.
    Journal of neuro-oncology, 2020, Volume: 149, Issue:3

    A hallmark of pediatric low-grade glioma (pLGG) is aberrant signaling of the mitogen activated protein kinase (MAPK) pathway. Hence, inhibition of MAPK signaling using small molecule inhibitors such as MEK inhibitors (MEKi) may be a promising strategy.. In this multi-center retrospective centrally reviewed study, we analyzed 18 patients treated with the MEKi trametinib for progressive pLGG as an individual treatment decision between 2015 and 2019. We have investigated radiological response as per central radiology review, molecular classification and investigator observed toxicity.. We observed 6 partial responses (PR), 2 minor responses (MR), and 10 stable diseases (SD) as best overall responses. Disease control rate (DCR) was 100% under therapy. Responses were observed in KIAA1549:BRAF- as well as neurofibromatosis type 1 (NF1)-driven tumors. Median treatment time was 12.5 months (range: 2 to 27 months). Progressive disease was observed in three patients after cessation of trametinib treatment within a median time of 3 (2-4) months. Therapy related adverse events occurred in 16/18 patients (89%). Eight of 18 patients (44%) experienced severe adverse events (CTCAE III and/or IV; most commonly skin rash and paronychia) requiring dose reduction in 6/18 patients (33%), and discontinuation of treatment in 2/18 patients (11%).. Trametinib was an active and feasible treatment for progressive pLGG leading to disease control in all patients. However, treatment related toxicity interfered with treatment in individual patients, and disease control after MEKi withdrawal was not sustained in a fraction of patients. Our data support in-class efficacy of MEKi in pLGGs and necessity for upfront randomized testing of trametinib against current standard chemotherapy regimens.

    Topics: Antineoplastic Agents; Child; Child, Preschool; Female; Follow-Up Studies; Glioma; Humans; Infant; Male; Prognosis; Pyridones; Pyrimidinones; Retrospective Studies

2020
Down-regulation of Aquaporin-1 mediates a microglial phenotype switch affecting glioma growth.
    Experimental cell research, 2020, 11-15, Volume: 396, Issue:2

    Aquaporin 1 (AQP1), a transmembrane protein that forms water channels, has previously been shown to facilitate growth and progression of many types of tumors by modulating tumor cell migration, proliferation and angiogenesis. Here, we determined the impact of AQP1 expression in the tumor environment on the progression of brain tumors. Primary microglia from wild type(WT) and AQP1 knockout(KO) mice were used to test AQP1 effect on microglia function by using Western blot, quantative PCR, in an experimental in vivo mouse glioma model and organotypic brain slice culture. Deletion of AQP1 in the host tissue significantly reduced the survival of the mice implanted with GL261 glioma cells. The density of glioma-associated microglia/macrophages was almost doubled in AQP1KO mice. We found that factors secreted from GL261 cells decrease microglial AQP1 expression via the MEK/ERK pathway, and that inhibition of this pathway with Trametinib reduced tumor growth and prolonged the survival of tumor bearing mice, an effect which required the presence of microglia. Deletion of AQP1 in cultured microglia resulted in an increase in migratory activity and a decrease in TLR4-dependent innate immune responses. Our study demonstrates a functional relevance of AQP1 expression in microglia and hints to AQP1 as a potential novel target for glioma therapy.

    Topics: Animals; Aquaporin 1; Astrocytes; Biomarkers, Tumor; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Progression; Down-Regulation; Gene Deletion; Gene Expression Regulation, Neoplastic; Glioma; Inflammation; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Phenotype; Pyridones; Pyrimidinones; RAW 264.7 Cells

2020
Trametinib Toxicities in Patients With Low-grade Gliomas and Diabetes Insipidus: Related Findings?
    Journal of pediatric hematology/oncology, 2020, Volume: 42, Issue:4

    Low-grade gliomas (LGG) represent the most common form of primary central nervous system tumor arising in childhood. There is growing evidence to support the role of the mitogen-activated protein kinase pathway in driving tumor growth and MEK inhibitors are being investigated in clinical trials for refractory and unresectable LGGs. As MEK inhibitors progress through clinical trials, drug toxicities have been identified. We report on 2 pediatric patients with LGG and known diabetes insipidus who developed severe hyponatraemia associated with significant decreases in desmopressin doses after starting trametinib. We review potential mechanisms for this sodium imbalance by examining the interaction between MEK inhibition and aquaporin channel physiology. We recommend close monitoring of serum sodium levels and clinical status in patients with diabetes insipidus who have optic-hypothalamic gliomas and are started on treatment with MEK inhibitors.

    Topics: Child; Diabetes Insipidus; Eye Neoplasms; Female; Glioma; Humans; Hypothalamic Neoplasms; Pyridones; Pyrimidinones

2020
Phosphoinositide-3-kinase inhibition elevates ferritin level resulting depletion of labile iron pool and blocking of glioma cell proliferation.
    Biochimica et biophysica acta. General subjects, 2019, Volume: 1863, Issue:3

    Elevated endogenous phosphoinositide-3-kinase (PI3K) activity is critical for cell proliferation in gliomas. Iron availability is one of the essential factors for cell growth and proliferation. However, any relation between PI3K and cellular iron homeostasis has not been understood so far.. Glioma cells and human primary astrocytes were treated with class I PI3K inhibitors to examine regulation of iron homeostasis components. Regulation of ferritin was detected at mRNA and translational level. Labile iron pool (LIP) and cell proliferation were examined in glioma cells and human primary astrocytes.. Blocking of PI3K activity elevated ferritin level by 6-10 folds in glioma cells by augmenting mRNA expression of ferritin subunits and also by influencing ferritin translation. IRE-IRP interaction was affected due to conversion of IRP1 to cytosolic aconitase that was influenced by increased iron-sulfur scaffold protein iron-sulfur cluster assembly enzyme (ISCU) level. Elevated ferritin sequestered LIP to affect cell proliferation that was reversed in silencing ferritin by siRNAs of ferritin-H and ISCU. Human primary astrocyte with little PI3K activity did not show any change in ferritin level, LIP and cell proliferation by PI3K inhibitors.. PI3K inhibition promotes ferritin synthesis by dual mechanism resulting sequestration of iron to limit its availability for cell proliferation in glioma cells but not in primary astrocytes.. This observation establishes a relation between PI3K signalling and iron homeostasis in glioma cells. It also implies that activated PI3K controls ferritin expression to ensure availability of adequate iron required for cell proliferation.

    Topics: Adenine; Animals; Brain Neoplasms; Cell Proliferation; Cells, Cultured; Chromones; Down-Regulation; Ferritins; Glioma; Humans; Iron; Morpholines; Phosphoinositide-3 Kinase Inhibitors; Pyrimidinones; Quinazolines; Rats; Thiazolidinediones; Up-Regulation

2019
Synthesis, Characterization, and Anticancer Activities Evaluation of Compounds Derived from 3,4-Dihydropyrimidin-2(1
    Molecules (Basel, Switzerland), 2019, Mar-03, Volume: 24, Issue:5

    3,4-dihydropyrimidin-2(1

    Topics: Alkylation; Animals; Antineoplastic Agents; Catalysis; Cell Line, Tumor; Glioma; Humans; Mice; Pyrimidinones; Solvents; Structure-Activity Relationship; Xenograft Model Antitumor Assays

2019
Oncolytic HSV therapy increases trametinib access to brain tumors and sensitizes them in vivo.
    Neuro-oncology, 2019, 09-06, Volume: 21, Issue:9

    Hyperactivation of the RAS-RAF-MEK-ERK signaling pathway is exploited by glioma cells to promote their growth and evade apoptosis. MEK activation in tumor cells can increase replication of ICP34.5-deleted herpes simplex virus type 1 (HSV-1), but paradoxically its activation in tumor-associated macrophages promotes a pro-inflammatory signaling that can inhibit virus replication and propagation. Here we investigated the effect of blocking MEK signaling in conjunction with oncolytic HSV-1 (oHSV) for brain tumors.. Infected glioma cells co-cultured with microglia or macrophages treated with or without trametinib were used to test trametinib effect on macrophages/microglia. Enzyme-linked immunosorbent assay, western blotting, and flow cytometry were utilized to evaluate the effect of the combination therapy. Pharmacokinetic (PK) analysis of mouse plasma and brain tissue was used to evaluate trametinib delivery to the CNS. Intracranial human and mouse glioma-bearing immune deficient and immune competent mice were used to evaluate the antitumor efficacy.. Oncolytic HSV treatment rescued trametinib-mediated feedback reactivation of the mitogen-activated protein kinase signaling pathway in glioma. In vivo, PK analysis revealed enhanced blood-brain barrier penetration of trametinib after oHSV treatment. Treatment by trametinib, a MEK kinase inhibitor, led to a significant reduction in microglia- and macrophage-derived tumor necrosis factor alpha (TNFα) secretion in response to oHSV treatment and increased survival of glioma-bearing mice. Despite the reduced TNFα production observed in vivo, the combination treatment activated CD8+ T-cell mediated immunity and increased survival in a glioma-bearing immune-competent mouse model.. This study provides a rationale for combining oHSV with trametinib for the treatment of brain tumors.

    Topics: Animals; Blood-Brain Barrier; Brain Neoplasms; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Disease Models, Animal; Glioblastoma; Glioma; Herpesvirus 1, Human; Humans; Immunocompetence; Macrophages; Mice; Microglia; Mitogen-Activated Protein Kinase Kinases; Oncolytic Virotherapy; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; RAW 264.7 Cells; Survival Rate; Tumor Necrosis Factor-alpha; Xenograft Model Antitumor Assays

2019
Antitumor immune response during glioma virotherapy.
    Neuro-oncology, 2019, 09-06, Volume: 21, Issue:9

    Topics: Brain Neoplasms; Glioma; Humans; Oncolytic Virotherapy; Pyridones; Pyrimidinones

2019
Rapid Clinical and Radiographic Response With Combined Dabrafenib and Trametinib in Adults With
    Journal of the National Comprehensive Cancer Network : JNCCN, 2018, Volume: 16, Issue:1

    Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Child; Child, Preschool; Female; Glioma; Humans; Imidazoles; Infant; Magnetic Resonance Imaging; Male; Molecular Targeted Therapy; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Radiography; Treatment Outcome

2018
Synthesis of pyrazolo[3,4-d]pyrimidin-4(5H)-ones tethered to 1,2,3-triazoles and their evaluation as potential anticancer agents.
    European journal of medicinal chemistry, 2018, Aug-05, Volume: 156

    A series of hybrid aza heterocycles containing pyrazolo[3,4-d]pyrimidin-4(5H)-ones tethered to 1,2,3-triazole scaffold were synthesized from 1,3-dipolar cycloaddition reaction of pyrazolopyrimidinone based alkyne with azides using Cu(II) catalyst in presence of sodium ascorbate and evaluated for their anticancer efficacy in vitro against C6 rat and U87 human glioma cell lines. These compounds induced a concentration dependent inhibition of C6 rat and U87 human glioma cell proliferation. Compound 5f arrested the cells at S-phase of the cell cycle and induced apoptosis in U87 GBM cell lines. Further, apoptosis was evidenced by the cleavage of Caspase-3, PARP and up regulation of p53. In silico docking studies reveal that the compounds 5a, 5f and 5l were more effective in binding with TGFBR2 than other compounds.

    Topics: Animals; Antineoplastic Agents; Apoptosis; Brain Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Chemistry Techniques, Synthetic; Drug Screening Assays, Antitumor; Glioma; Humans; Molecular Docking Simulation; Protein Serine-Threonine Kinases; Pyrazoles; Pyrimidinones; Rats; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Triazoles

2018
The β-catenin/CBP-antagonist ICG-001 inhibits pediatric glioma tumorigenicity in a Wnt-independent manner.
    Oncotarget, 2017, Apr-18, Volume: 8, Issue:16

    Pediatric high-grade gliomas (pedHGG) belong to the most aggressive cancers in children with a poor prognosis due to a lack of efficient therapeutic strategies. The β-catenin/Wnt-signaling pathway was shown to hold promising potential as a treatment target in adult high-grade gliomas by abrogating tumor cell invasion and the acquisition of stem cell-like characteristics. Since pedHGG differ from their adult counterparts in genetically and biologically we aimed to investigate the effects of β-catenin/Wnt-signaling pathway-inhibition by the β-catenin/CBP antagonist ICG-001 in pedHGG cell lines. In contrast to adult HGG, pedHGG cells displayed minimal detectable canonical Wnt-signaling activity. Nevertheless, low doses of ICG-001 inhibited cell migration/invasion, tumorsphere- and colony formation, proliferation in vitro as well as tumor growth in vivo/ovo, suggesting that ICG-001 affects pedHGG tumor cell characteristics independent of β-catenin/Wnt-signaling. RNA-sequencing analyses support a Wnt/β-catenin-independent effect of ICG-001 on target gene transcription, revealing strong effects on genes involved in cellular metabolic/biosynthetic processes and cell cycle progression. Among these, high mRNA expression of cell cycle regulator JDP2 was found to confer a better prognosis for pedHGG patients. In conclusion, ICG-001 might offer an effective treatment option for pedHGG patients functioning to regulate cell phenotype and gene expression programs in absence of Wnt/β-catenin signaling-activity.

    Topics: Adolescent; Animals; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Movement; Cell Self Renewal; Cell Survival; Cell Transformation, Neoplastic; Chick Embryo; Child; Child, Preschool; CREB-Binding Protein; Databases, Genetic; Disease Models, Animal; Glioma; Humans; Kaplan-Meier Estimate; Neoplastic Stem Cells; Prognosis; Pyrimidinones; Wnt Signaling Pathway; Young Adult

2017
Dabrafenib and trametinib in BRAFV600E mutated glioma.
    CNS oncology, 2017, Volume: 6, Issue:4

    BRAFV600E mutations have been identified in a number of glioma subtypes, most frequently in pleomorphic xanthoastrocytoma, ganglioglioma, pilocytic astrocytoma, and epithelioid glioblastoma. Although the development of BRAF inhibitors has dramatically improved the clinical outcome for patients with BRAFV600E mutant tumors, resistance develops in a majority of patients due to reactivation of the MAPK pathway. Addition of MEK inhibition to BRAF inhibition improves survival. Here we report successful treatment of two patients with BRAFV600E mutant pleomorphic xanthoastrocytoma using the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib.

    Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Female; Glioma; Humans; Imidazoles; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2017
Tetrandrine inhibits glioma stem-like cells by repressing β-catenin expression.
    International journal of oncology, 2017, Volume: 50, Issue:1

    Cancer stem cells (CSCs) in glioma are often responsible for relapse and resistance to therapy. The purpose of the present study was to confirm the self-renewal and migration inhibitory effects of tetrandrine (Tet), which is a compound extracted from the dried root of Stephania tetrandra S. Moore, toward glioma stem-like cells (GSLCs) and to examine the associated molecular mechanisms. Using a neurosphere culture technique, we enriched the GSLC population from the human glioblastoma cell lines U87 and U251. Cells were analyzed using cell counting kit-8 (CCK-8), western blotting, flow cytometry, transwell assay and immunofluorescence staining. GSLCs displayed properties of neural stem cells, including elevated expression of the cancer stem cell marker ALDH1 and β-catenin. We found that Tet treatment decreased sphere formation in GSLCs in a dose-dependent manner using tumor spheroid formation assay. The GSK3β inhibitor BIO maintained sphere formation and migration capacity in GSLCs, whereas the β-catenin/TCF transcription inhibitor ICG-001 decreased sphere formation and the migration capacity of GSLCs. The proportion of apoptotic GSLCs also increased in response to ICG-001 treatment. These results indicate that β-catenin activity is vital in maintaining neural stem cell traits of GSLCs. Tet inhibits cell viability, neurosphere formation and migration of GSLCs in vitro. Importantly, Tet treatment significantly repressed the nuclear translocation and expression of β-catenin and induced apoptosis in GSLCs, as indicated in part by the upregulation of Bax, the cleavage of PARP and the downregulation of Bcl-2. The present study demonstrates that the inhibition of β-catenin in CSCs by Tet could be an effective strategy for the treatment of glioma.

    Topics: Apoptosis; bcl-2-Associated X Protein; Benzylisoquinolines; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Glioma; Humans; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Pyrimidinones

2017
Dabrafenib Effective in Pediatric Glioma.
    Cancer discovery, 2017, Volume: 7, Issue:1

    A phase I/II clinical trial suggests that dabrafenib shrinks or stabilizes low-grade gliomas in children with the BRAF V600E mutation. Objective, durable responses occurred in 38% of patients, and the side effects were less severe than with chemotherapy. The researchers have started a second trial for patients with glioma and other BRAF-mutant tumor types, this time evaluating dabrafenib combined with trametinib.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Child; Clinical Trials as Topic; Disease-Free Survival; Female; Glioma; Humans; Imidazoles; Male; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Analysis; Treatment Outcome

2017
Towards longitudinal mapping of extracellular pH in gliomas.
    NMR in biomedicine, 2016, Volume: 29, Issue:10

    Biosensor imaging of redundant deviation in shifts (BIRDS), an ultrafast chemical shift imaging technique, requires infusion of paramagnetic probes such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis methylene phosphonate (DOTP(8-) ) complexed with thulium (Tm(3+) ) ion (i.e. TmDOTP(5-) ), where the pH-sensitive resonances of hyperfine-shifted non-exchangeable protons contained within the paramagnetic probe are detected. While imaging extracellular pH (pHe ) with BIRDS meets an important cancer research need by mapping the intratumoral-peritumoral pHe gradient, the surgical intervention used to raise the probe's plasma concentration limits longitudinal scans on the same subject. Here we describe using probenecid (i.e. an organic anion transporter inhibitor) to temporarily restrict renal clearance of TmDOTP(5-) , thereby facilitating molecular imaging by BIRDS without surgical intervention. Co-infusion of probenecid with TmDOTP(5-) increased the probe's distribution into various organs, including the brain, compared with infusing TmDOTP(5-) alone. In vivo BIRDS data using the probenecid-TmDOTP(5-) co-infusion method in rats bearing RG2, 9 L, and U87 brain tumors showed intratumoral-peritumoral pHe gradients that were unaffected by the probe dose. This co-infusion method can be used for pHe mapping with BIRDS in preclinical models for tumor characterization and therapeutic monitoring, given the possibility of repeated scans with BIRDS (e.g. over days and even weeks) in the same subject. The longitudinal pHe readout by the probenecid-TmDOTP(5-) co-infusion method for BIRDS adds translational value in tumor assessment and treatment. Copyright © 2016 John Wiley & Sons, Ltd.

    Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Glioma; Hydrogen-Ion Concentration; Magnetic Resonance Imaging; Male; Molecular Probe Techniques; Molecular Probes; Oxazoles; Pyrimidinones; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity

2016
GSK621 Targets Glioma Cells via Activating AMP-Activated Protein Kinase Signalings.
    PloS one, 2016, Volume: 11, Issue:8

    Here, we studied the anti-glioma cell activity by a novel AMP-activated protein kinase (AMPK) activator GSK621. We showed that GSK621 was cytotoxic to human glioma cells (U87MG and U251MG lines), possibly via provoking caspase-dependent apoptotic cell death. Its cytotoxicity was alleviated by caspase inhibitors. GSK621 activated AMPK to inhibit mammalian target of rapamycin (mTOR) and downregulate Tetraspanin 8 (Tspan8) in glioma cells. AMPK inhibition, through shRNA knockdown of AMPKα or introduction of a dominant negative (T172A) AMPKα, almost reversed GSK621-induced AMPK activation, mTOR inhibition and Tspan8 degradation. Consequently, GSK621's cytotoxicity in glioma cells was also significantly attenuated by AMPKα knockdown or mutation. Further studies showed that GSK621, at a relatively low concentration, significantly potentiated temozolomide (TMZ)'s sensitivity and lethality against glioma cells. We summarized that GSK621 inhibits human glioma cells possibly via activating AMPK signaling. This novel AMPK activator could be a novel and promising anti-glioma cell agent.

    Topics: AMP-Activated Protein Kinases; Antineoplastic Agents; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Cell Survival; Dacarbazine; Down-Regulation; Drug Resistance, Neoplasm; Enzyme Activation; Gene Knockdown Techniques; Glioma; Humans; Imidazoles; Pyrimidinones; Signal Transduction; Temozolomide; Tetraspanins; TOR Serine-Threonine Kinases

2016
WEE1 kinase inhibition enhances the radiation response of diffuse intrinsic pontine gliomas.
    Molecular cancer therapeutics, 2013, Volume: 12, Issue:2

    Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric disease. Thus far, no therapeutic agent has proven beneficial in the treatment of this malignancy. Therefore, conventional DNA-damaging radiotherapy remains the standard treatment, providing transient neurologic improvement without improving the probability of overall survival. During radiotherapy, WEE1 kinase controls the G(2) cell-cycle checkpoint, allowing for repair of irradiation (IR)-induced DNA damage. Here, we show that WEE1 kinase is one of the highest overexpressed kinases in primary DIPG tissues compared with matching non-neoplastic brain tissues. Inhibition of WEE1 by MK-1775 treatment of DIPG cells inhibited the IR-induced WEE1-mediated phosphorylation of CDC2, resulting in reduced G(2)-M arrest and decreased cell viability. Finally, we show that MK-1775 enhances the radiation response of E98-Fluc-mCherry DIPG mouse xenografts. Altogether, these results show that inhibition of WEE1 kinase in conjunction with radiotherapy holds potential as a therapeutic approach for the treatment of DIPG.

    Topics: Animals; Brain Stem Neoplasms; Cell Cycle Proteins; Combined Modality Therapy; Female; Glioma; Humans; Immunohistochemistry; Mice; Mice, Nude; Nuclear Proteins; Phosphorylation; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; Radiation-Sensitizing Agents; Random Allocation; Xenograft Model Antitumor Assays

2013
MC540 induced photosensitization of glioma & neuroblastoma cells.
    The Indian journal of medical research, 1994, Volume: 99

    Binding and photodynamic action of merocyanine 540 (MC540) has been studied in glioma (U-87MG) and neuroblastoma (Neuro 2A) cells as a function of dye concentration, incubation time of cells with MC540 and growth phase of cells. In the plateau phase, U-87MG cells accumulated more MC540 as compared to exponentially growing cells, whereas in Neuro 2A cells the opposite effect was observed. Exponentially growing U-87MG cells were more photosensitive than plateau phase cells. However, the photosensitivity of Neuro 2A cells was not dependent on the growth phase. Thus, MC540 mediated photosensitization may be useful for photodynamic therapy of brain tumours.

    Topics: Fluorescent Dyes; Glioma; Neuroblastoma; Photochemotherapy; Photosensitizing Agents; Pyrimidinones; Staining and Labeling; Tumor Cells, Cultured

1994
Effects of bradykinin, GTP gamma S, R59022 and N-ethylmaleimide on inositol phosphate production in NG108-15 cells.
    Biochemical and biophysical research communications, 1989, Nov-30, Volume: 165, Issue:1

    Accumulation of inositol phosphates in NG108-15 neuroblastoma x glioma hybrid cells, pre-labeled for 24h to equilibrium, was stimulated by bradykinin, guanosine 5'-O-(3-thiotriphosphate) and the diacylglycerol kinase inhibitor R59022. Only the stimulation by bradykinin was inhibited by the bradykinin receptor antagonist [D-Arg0, Hyp3, Phe7, Thi5,8] bradykinin. Neither bradykinin nor R059022 increased the labeling of the inositol phospholipids. The sulfhydryl-alkylating reagent N-ethylmaleimide at 100 microM essentially abolished the stimulation caused by all three agents, possibly by preventing the binding of GTP to a guanine nucleotide-binding regulatory protein of as yet unknown size.

    Topics: Animals; Bradykinin; Cell Line; Drug Interactions; Ethylmaleimide; Glioma; Guanosine 5'-O-(3-Thiotriphosphate); Guanosine Triphosphate; Hybrid Cells; Inositol; Inositol Phosphates; Kinetics; Mice; Neuroblastoma; Platelet Activating Factor; Pyrimidinones; Rats; Thiazoles; Thionucleotides

1989