Intratumoral retrograde microdialysis treatment of high-grade glioma with cisplatin

Tabatabaei, Pedram; Asklund, Thomas; Bergström, Per; Björn, Erik; Johansson, Mikael; Bergenheim, A. Tommy

doi:10.1007/s00701-020-04488-2

Cited by 5 publications

(3 citation statements)

References 25 publications

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“…Cisplatin was one of the adjuvant reagents for glioma chemotherapy [ 134 ]. It can form adducts with cellular DNA and lead to cell-cycle arrest and apoptosis [ 135 ].…”

Section: Aa Metabolism and Glioma Chemotherapy Sensitivitiesmentioning

confidence: 99%

Rewired Metabolism of Amino Acids and Its Roles in Glioma Pathology

et al. 2022

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Amino acids (AAs) are indispensable building blocks of diverse bio-macromolecules as well as functional regulators for various metabolic processes. The fact that cancer cells live with a voracious appetite for specific AAs has been widely recognized. Glioma is one of the most lethal malignancies occurring in the central nervous system. The reprogrammed metabolism of AAs benefits glioma proliferation, signal transduction, epigenetic modification, and stress tolerance. Metabolic alteration of specific AAs also contributes to glioma immune escape and chemoresistance. For clinical consideration, fluctuations in the concentrations of AAs observed in specific body fluids provides opportunities to develop new diagnosis and prognosis markers. This review aimed at providing an extra dimension to understanding glioma pathology with respect to the rewired AA metabolism. A deep insight into the relevant fields will help to pave a new way for new therapeutic target identification and valuable biomarker development.

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“…Cisplatin was one of the adjuvant reagents for glioma chemotherapy [ 134 ]. It can form adducts with cellular DNA and lead to cell-cycle arrest and apoptosis [ 135 ].…”

Section: Aa Metabolism and Glioma Chemotherapy Sensitivitiesmentioning

confidence: 99%

Rewired Metabolism of Amino Acids and Its Roles in Glioma Pathology

et al. 2022

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“…Although cisplatin has been shown to have cytotoxic effects on human glioblastoma cells in vitro [ 20 , 41 ] the response in clinical treatment is weak and has not improved the overall survival of patients with brain tumours. Anyway, many studies are currently focused on new delivery modalities of effective cisplatin in GBM [ 2 , 6 , 37 , 43 ]. The mechanism of action of cisplatin is mainly based on DNA damage, inducing the formation of DNA adducts.…”

Section: Introductionmentioning

confidence: 99%

KRAS is a molecular determinant of platinum responsiveness in glioblastoma

Zuchegna,

Leone,

Romano

et al. 2024

BMC Cancer

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Background KRAS is the undisputed champion of oncogenes, and despite its prominent role in oncogenesis as mutated gene, KRAS mutation appears infrequent in gliomas. Nevertheless, gliomas are considered KRAS-driven cancers due to its essential role in mouse malignant gliomagenesis. Glioblastoma is the most lethal primary brain tumor, often associated with disturbed RAS signaling. For newly diagnosed GBM, the current standard therapy is alkylating agent chemotherapy combined with radiotherapy. Cisplatin is one of the most effective anticancer drugs and is used as a first-line treatment for a wide spectrum of solid tumors (including medulloblastoma and neuroblastoma) and many studies are currently focused on new delivery modalities of effective cisplatin in glioblastoma. Its mechanism of action is mainly based on DNA damage, inducing the formation of DNA adducts, triggering a series of signal-transduction pathways, leading to cell-cycle arrest, DNA repair and apoptosis. Methods Long-term cultures of human glioblastoma, U87MG and U251MG, were either treated with cis-diamminedichloroplatinum (cisplatin, CDDP) and/or MEK-inhibitor PD98059. Cytotoxic responses were assessed by cell viability (MTT), protein expression (Western Blot), cell cycle (PI staining) and apoptosis (TUNEL) assays. Further, gain-of-function experiments were performed with cells over-expressing mutated hypervariable region (HVR) KRASG12V plasmids. Results Here, we studied platinum-based chemosensitivity of long-term cultures of human glioblastoma from the perspective of KRAS expression, by using CDDP and MEK-inhibitor. Endogenous high KRAS expression was assessed at transcriptional (qPCR) and translational levels (WB) in a panel of primary and long-term glioblastoma cultures. Firstly, we measured immediate cellular adjustment through direct regulation of protein concentration of K-Ras4B in response to cisplatin treatment. We found increased endogenous protein abundance and involvement of the effector pathway RAF/MEK/ERK mitogen-activated protein kinase (MAPK) cascade. Moreover, as many MEK inhibitors are currently being clinically evaluated for the treatment of high-grade glioma, so we concomitantly tested the effect of the potent and selective non-ATP-competitive MEK1/2 inhibitor (PD98059) on cisplatin-induced chemosensitivity in these cells. Cell-cycle phase distribution was examined using flow cytometry showing a significant cell-cycle arrest in both cultures at different percentage, which is modulated by MEK inhibition. Cisplatin-induced cytotoxicity increased sub-G1 percentage and modulates G2/M checkpoint regulators cyclins D1 and A. Moreover, ectopic expression of a constitutively active KRASG12V rescued CDDP-induced apoptosis and different HVR point mutations (particularly Ala 185) reverted this phenotype. Conclusion These findings warrant further studies of clinical applications of MEK1/2 inhibitors and KRAS as ‘actionable target’ of cisplatin-based chemotherapy for glioblastoma.

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“…Many targeted drug delivery techniques have been proposed to overcome this challenge 1,2 . For nonresectable tumours in particular, the possibility to insert catheters or implants, analogously to standard biopsy procedures, has been explored in a variety of ways, for example in Convection-Enhanced Delivery (CED) [3][4][5][6] , electrokinetic 7 or electrophoretic 8 delivery, gel implants 9,10 , or retrodialysis 2,[11][12][13][14][15][16][17][18] .…”

mentioning

confidence: 99%

Quantitative monitoring and modelling of retrodialysis drug delivery in a brain phantom

Rognin

Willis‐Fox

Daly

2023

Sci Rep

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A vast number of drug molecules are unable to cross the blood-brain barrier, which results in a loss of therapeutic opportunities when these molecules are administered by intravenous infusion. To circumvent the blood-brain barrier, local drug delivery devices have been developed over the past few decades such as reverse microdialysis. Reverse microdialysis (or retrodialysis) offers many advantages, such as a lack of net volume influx to the intracranial cavity and the ability to sample the tumour’s micro-environment. However, the translation of this technique to efficient drug delivery has not been systematically studied. In this work, we present an experimental platform to evaluate the performance of microdialysis devices in reverse mode in a brain tissue phantom. The mass of model drug delivered is measured by computing absorbance fields from optical images. Concentration maps are reconstructed using a modern and open-source implementation of the inverse Abel transform. To illustrate our method, we assess the capability of a commercial probe in delivering methylene blue to a gel phantom. We find that the delivery rate can be described by classical microdialysis theory, except at low dialysate flow rates where it is impacted by gravity, and high flow rates where significant convection to the gel occurs. We also show that the flow rate has an important impact not only on the overall size of the drug plume, but also on its shape. The numerical tools developed for this study have been made freely available to ensure that the method presented can be used to rapidly and inexpensively optimise probe design and protocol parameters before proceeding to more in-depth studies.

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Intratumoral retrograde microdialysis treatment of high-grade glioma with cisplatin

Cited by 5 publications

References 25 publications

Rewired Metabolism of Amino Acids and Its Roles in Glioma Pathology

Rewired Metabolism of Amino Acids and Its Roles in Glioma Pathology

KRAS is a molecular determinant of platinum responsiveness in glioblastoma

Quantitative monitoring and modelling of retrodialysis drug delivery in a brain phantom

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