Medulloblastoma in childhood: revisiting intrathecal therapy in infants and children

Conroy, Sharon; Garnett, Martin C.; Vloeberghs, Michael; Grundy, Richard G.; Craven, Ian; Walker, David

doi:10.1007/s00280-009-1127-1

Cited by 14 publications

(5 citation statements)

References 117 publications

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“…The topoisomerase inhibitor etoposide [44] was picked as the drug of choice because it has shown promising activity against medulloblastoma in vivo [45] and has been investigated as a potential candidate for intrathecal therapy [4], [46]. The main therapeutic merit of etoposide is seen as a way of reducing craniospinal radiation in young medulloblastoma patients in whom it could reduce the serious side effects associated with radiotherapy [47].…”

Section: Resultsmentioning

confidence: 99%

“…To enhance selectivity, better methods for drug delivery are needed to improve the effectiveness of medulloblastoma chemotherapy. Strategies to enhance the selectivity of etoposide could be using an etoposide-bearing drug-delivery system [64]–[66] that primarily targets tumour tissue or intrathecal therapy [4] to target leptomeningeal tumour tissue.…”

Section: Discussionmentioning

confidence: 99%

“…This simple reductionist model offered by monolayers bears little resemblance to the in-vivo situation and the results obtained rarely coincide with the outcomes of clinical trials [3]. Our interest in improving drug delivery to the brain [4] has pointed the need for establishing superior preclinical models to characterise the safety and efficacy of cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

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Multiplexing Spheroid Volume, Resazurin and Acid Phosphatase Viability Assays for High-Throughput Screening of Tumour Spheroids and Stem Cell Neurospheres

et al. 2014

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Three-dimensional cell culture has many advantages over monolayer cultures, and spheroids have been hailed as the best current representation of small avascular tumours in vitro. However their adoption in regular screening programs has been hindered by uneven culture growth, poor reproducibility and lack of high-throughput analysis methods for 3D. The objective of this study was to develop a method for a quick and reliable anticancer drug screen in 3D for tumour and human foetal brain tissue in order to investigate drug effectiveness and selective cytotoxic effects. Commercially available ultra-low attachment 96-well round-bottom plates were employed to culture spheroids in a rapid, reproducible manner amenable to automation. A set of three mechanistically different methods for spheroid health assessment (Spheroid volume, metabolic activity and acid phosphatase enzyme activity) were validated against cell numbers in healthy and drug-treated spheroids. An automated open-source ImageJ macro was developed to enable high-throughput volume measurements. Although spheroid volume determination was superior to the other assays, multiplexing it with resazurin reduction and phosphatase activity produced a richer picture of spheroid condition. The ability to distinguish between effects on malignant and the proliferating component of normal brain was tested using etoposide on UW228-3 medulloblastoma cell line and human neural stem cells. At levels below 10 µM etoposide exhibited higher toxicity towards proliferating stem cells, whereas at concentrations above 10 µM the tumour spheroids were affected to a greater extent. The high-throughput assay procedures use ready-made plates, open-source software and are compatible with standard plate readers, therefore offering high predictive power with substantial savings in time and money.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multiplexing Spheroid Volume, Resazurin and Acid Phosphatase Viability Assays for High-Throughput Screening of Tumour Spheroids and Stem Cell Neurospheres

et al. 2014

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“…It has been studied both as an alternative and an addition to radiotherapy [9,10]. Pharmacokinetic studies have shown cytotoxic drug levels in the cerebrospinal fluid for 1-2 weeks in children as well as in adults [11][12][13].…”

Section: Discussionmentioning

confidence: 99%

Treatment for recurrent medulloblastoma with intrathecal liposomal cytarabine and systemic metronomic combination therapy

Nygaard

Kivivuori²

2012

Anti-Cancer Drugs

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The prognosis of recurrent medulloblastoma is dismal, with a median survival of less than 1 year. Our patient was initially diagnosed with high-risk medulloblastoma when he was 14 years old. He had a recurrence 18 months after the end of therapy. Recurrence treatment consisted of 13 intrathecal applications of liposomal cytarabine over an 18-month period, and oral metronomic antiangiogenic therapy with thalidomide, celecoxib, and etoposide. Side effects from the intrathecal treatment were most likely related to arachnoiditis despite prolonged prophylaxis with steroids. He also developed partial hearing loss. Neutropenia was the main side effect of the metronomic therapy. He remains alive, with a good quality of life and without evidence of disease 34 months from the start of recurrence therapy. This combination of local antineoplastic and systemic antiangiogenic therapy seems to be promising for recurrent medulloblastoma. However, more patients and standardized protocols are needed to verify the benefit of this combination therapy and to define the correct duration of treatment.

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“…Furthermore, existing approved drugs might have been discounted for development as a brain tumor treatment due to their inability to reach the brain. By harnessing the new delivery techniques that are in development, these should now be reconsidered and evaluated as potential brain tumor treatments [16]. The World Health Organization (WHO) has recently made a powerful economic case for commissioning child cancer therapies globally to exploit a 3:1 economic payback in societal terms [17].…”

Section: Introductionmentioning

confidence: 99%

Childhood Brain Tumors: A Review of Strategies to Translate CNS Drug Delivery to Clinical Trials

Rahman

Janowski

Killick-Cole

et al. 2023

Cancers

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Brain and spinal tumors affect 1 in 1000 people by 25 years of age, and have diverse histological, biological, anatomical and dissemination characteristics. A mortality of 30–40% means the majority are cured, although two-thirds have life-long disability, linked to accumulated brain injury that is acquired prior to diagnosis, and after surgery or chemo-radiotherapy. Only four drugs have been licensed globally for brain tumors in 40 years and only one for children. Most new cancer drugs in clinical trials do not cross the blood–brain barrier (BBB). Techniques to enhance brain tumor drug delivery are explored in this review, and cover those that augment penetration of the BBB, and those that bypass the BBB. Developing appropriate delivery techniques could improve patient outcomes by ensuring efficacious drug exposure to tumors (including those that are drug-resistant), reducing systemic toxicities and targeting leptomeningeal metastases. Together, this drug delivery strategy seeks to enhance the efficacy of new drugs and enable re-evaluation of existing drugs that might have previously failed because of inadequate delivery. A literature review of repurposed drugs is reported, and a range of preclinical brain tumor models available for translational development are explored.

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Medulloblastoma in childhood: revisiting intrathecal therapy in infants and children

Cited by 14 publications

References 117 publications

Multiplexing Spheroid Volume, Resazurin and Acid Phosphatase Viability Assays for High-Throughput Screening of Tumour Spheroids and Stem Cell Neurospheres

Multiplexing Spheroid Volume, Resazurin and Acid Phosphatase Viability Assays for High-Throughput Screening of Tumour Spheroids and Stem Cell Neurospheres

Treatment for recurrent medulloblastoma with intrathecal liposomal cytarabine and systemic metronomic combination therapy

Childhood Brain Tumors: A Review of Strategies to Translate CNS Drug Delivery to Clinical Trials

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