Cisplatin, ara-C and etoposide (PAE) in the treatment of recurrent childhood brain tumors

Corden, Brian J.; Strauss, Lewis C.; Killmond, Thomas M.; Carson, Benjamin S.; Wharam, Moody D.; Kumar, Ashok J.; Piantadosi, Steven; Robb, Pam A.; Phillips, Peter C.B.

doi:10.1007/bf00166998

Cited by 31 publications

(12 citation statements)

References 14 publications

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“…47 Therefore, 25 lM fenofibrate holds promise for low toxicity systemic chemotherapy against medulloblastoma in comparison to current regimens many of which are highly toxic. 48,49 In human medulloblastoma cells, Daoy and D384, which express PPARa and PPARg, 25 lM fenofibrate attenuated IGF-I-mediated signaling events including IRS-1, Akt, ERKs and GSK-3b phosphorylation (Fig. 5a), and triggered cell cycle arrest (Fig.…”

Section: Discussionmentioning

confidence: 99%

Activation of PPARα inhibits IGF‐I‐mediated growth and survival responses in medulloblastoma cell lines

Urbańska

Pannizzo

Grabacka

et al. 2008

Intl Journal of Cancer

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Recent studies suggest a potential role of lipid lowering drugs, fibrates and statins, in anticancer treatment. One candidate for tumor chemoprevention is fenofibrate, which is a potent agonist of peroxisome proliferator activated receptor alpha (PPARa). Our results demonstrate elevated expression of PPARa in the nuclei of neoplatic cells in 12 out of 13 cases of medulloblastoma, and of PPARc in six out of 13 cases. Further analysis demonstrated that aggressive mouse medulloblastoma cells, BsB8, express PPARa in the absence PPARc, and human medulloblastoma cells, D384 and Daoy, express both PPARa and PPARc. Mouse and human cells responded to fenofibrate by a significant increase of PPAR-mediated transcriptional activity, and by a gradual accumulation of cells in G1 and G2/M phase of the cell cycle, leading to the inhibition of cell proliferation and elevated apoptosis. Preincubation of BsB8 cells with fenofibrate attenuated IGF-I-induced IRS-1, Akt, ERKs and GSK3b phosphorylation, and inhibited clonogenic growth. In Daoy and D384 cells, fenofibrate also inhibited IGF-I-mediated growth responses, and simultaneous delivery of fenofibrate with low dose of the IGF-IR inhibitor, NVP-AEW541, completely abolished their clonogenic growth and survival. These results indicate a strong supportive role of fenofibrate in chemoprevention against IGF-Iinduced growth responses in medulloblastoma. ' 2008 Wiley-Liss, Inc.Key words: PPARa; fenofibrate; IGF-I; medulloblastoma Medulloblastomas are highly malignant cerebellar tumors of the childhood, which originate from the external granule layer of the cerebellum and have an inherent tendency to spread in the CNS via cerebrospinal fluid. Medulloblastomas are characterized by a large number of genetic and epigenetic aberrations. 1 Among them, overexpression of insulin-like growth factor receptor (IGF-IR), and insulin receptor substrate 1 (IRS-1) are frequently seen in these tumors. [1][2][3][4][5] The IGF-IR is a membrane-associated tyrosine kinase capable of mediating a variety of biological responses including cell survival and cell proliferation. 6,7 In the cerebellum, the IGF-IR has been shown in the granule cell layer and in Purkinje cells, and IGF-I protected cultures of cerebellar neurons from low potassium induced apoptosis. 8,9 In medulloblastoma, the IGF-IR signaling system has been investigated quite intensively. 4,10 Resent results from our laboratory demonstrate that medulloblastoma cell lines and medulloblastoma biopsies are characterized by an abundant presence of the IGF-IR, and its major signaling molecule, IRS-1. 2,3 Importantly, we have detected the phosphorylated form of the IGF-IR (active) in the majority of medulloblastoma clinical samples examined. 2 In addition, growth and survival of medulloblastoma cell lines cultured in suspension was strongly dependent on the presence of exogenous IGF-I. 2,3 The low-molecular-weight inhibitor of the IGF-IR, NVP-AEW541, is one of the most effective inhibitors of the growth of medulloblastoma cells and induces massive apop...

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Section: Discussionmentioning

confidence: 99%

Activation of PPARα inhibits IGF‐I‐mediated growth and survival responses in medulloblastoma cell lines

Urbańska

Pannizzo

Grabacka

et al. 2008

Intl Journal of Cancer

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“…A total of 30% of 5-year survival has been reported for medulloblastoma of this location after surgery and radiotherapy [22,23] . Chemotherapy has also been combined with radiotherapy with improvement in some cases [24] .…”

Section: Discussionmentioning

confidence: 99%

Extra-Axial Cerebellopontine Angle Medulloblastoma in an Infant

Bhaskar

Jaiswal²,

Ojha³

et al. 2017

Pediatr Neurosurg

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Medulloblastoma is a common tumor of the posterior fossa, representing 20-25% of all pediatric neoplasms. It commonly occurs in the midline (cerebellar vermis) and rarely at the cerebellopontine angle. Most of them are intra-axial, and an extra-axial location of this tumor is very rare. Extra-axial cerebellopontine angle medulloblastoma is extremely uncommon and has never been reported in an infant. We report an extra-axial cerebellopontine anglemedulloblastoma in a 1-year-old child.

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“…None of these trials identifed more than a 20% response rate, the highest being with oral etoposide, although this was based upon two studies where only 15 patients were studied in total. A similar literature review of phase 2 trials of drug combinations including cisplatin/cytarabine/etoposide,64cisplatin/cyclophosphamide,65mustine/vincristine/procarbazine/prednisolone,66 and thiotepa/etoposide given in high dose with autologous bone marrow rescue,67 failed to identified any of these combinations as being capable of producing a measurable sustained responses. The current UKCCSG brain stem glioma study is investigating tamoxifen, given in parallel with radiotherapy and at high dose (120 mg/m 2 /day) continously in newly diagnosed patients with diffuse intrinsic brain stem glioma.…”

Section: The Role Of Chemotherapymentioning

confidence: 99%

Clinical management of brain stem glioma

Walker

Punt

Sokal

1999

Archives of Disease in Childhood

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Brain and spinal tumours in childhood (0-15 years) account for 20-25% of childhood cancer, aVecting one in 2500 children. In the UK, this means that about 350 new cases are diagnosed each year, of which 55% and 50% survive five and 10 years, respectively.1 For those who are survivors, about 60% have cognitive deficits and 20-30% have diYculties with mobility and chronic pain.2 Deaths from this group of tumours in England and Wales account for the loss of over 10 000 life years each year (C Stiller, personal communication, 1995). 1Within the group of brain and spinal tumours there are a number of well defined categories with characteristic clinical presentations, biological behaviour, and suitability for specific treatment approaches. These factors combine to predict a range of outcomes from the highly curable tumours (> 80% 10 year survival rate) such as germinoma and cerebellar astrocytoma, through to the virtually incurable brain stem glioma.

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Cisplatin, ara-C and etoposide (PAE) in the treatment of recurrent childhood brain tumors

Cited by 31 publications

References 14 publications

Activation of PPARα inhibits IGF‐I‐mediated growth and survival responses in medulloblastoma cell lines

Activation of PPARα inhibits IGF‐I‐mediated growth and survival responses in medulloblastoma cell lines

Extra-Axial Cerebellopontine Angle Medulloblastoma in an Infant

Clinical management of brain stem glioma

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