Effective conversion of irinotecan to SN-38 after intratumoral drug delivery to an intracranial murine glioma model in vivo

Ghandi, Alex; Liebes, Leonard; Louie, Stan G.; Hofman, Florence M.; Schönthal, Axel H.; Chen, Thomas C.

doi:10.3171/2010.2.jns09719

Cited by 19 publications

(17 citation statements)

References 21 publications

(21 reference statements)

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“…The U251 line possesses considerable biotransformational activity [46] and is widely used as a cytotoxic model for a range of disparate agents such as ethanol and trimethyl tin chloride at concentrations which were within the range shown in human and other mammalian cellular systems [47]–[50]. The U251 line is also a relevant model of human astrocytes, demonstrating comparable susceptibility to glial toxins such as 6-hydroxydopamine in other models [47], [51].…”

Section: Resultsmentioning

confidence: 97%

A Preliminary Investigation into the Impact of a Pesticide Combination on Human Neuronal and Glial Cell Lines In Vitro

et al. 2012

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Many pesticides are used increasingly in combinations during crop protection and their stability ensures the presence of such combinations in foodstuffs. The effects of three fungicides, pyrimethanil, cyprodinil and fludioxonil, were investigated together and separately on U251 and SH-SY5Y cells, which can be representative of human CNS glial and neuronal cells respectively. Over 48h, all three agents showed significant reductions in cellular ATP, at concentrations that were more than tenfold lower than those which significantly impaired cellular viability. The effects on energy metabolism were reflected in their marked toxic effects on mitochondrial membrane potential. In addition, evidence of oxidative stress was seen in terms of a fall in cellular thiols coupled with increases in the expression of enzymes associated with reactive species formation, such as GSH peroxidase and superoxide dismutase. The glial cell line showed significant responsiveness to the toxin challenge in terms of changes in antioxidant gene expression, although the neuronal SH-SY5Y line exhibited greater vulnerability to toxicity, which was reflected in significant increases in caspase-3 expression, which is indicative of the initiation of apoptosis. Cyprodinil was the most toxic agent individually, although oxidative stress-related enzyme gene expression increases appeared to demonstrate some degree of synergy in the presence of the combination of agents. This report suggests that the impact of some pesticides, both individually and in combinations, merits further study in terms of their impact on human cellular health.

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Section: Resultsmentioning

confidence: 97%

A Preliminary Investigation into the Impact of a Pesticide Combination on Human Neuronal and Glial Cell Lines In Vitro

et al. 2012

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“…In the later period, there were significant differences between the PG1 and PG2 membranes at 58 days for 251 cells and 37 days for U87 cells ( p < 0.05). The obvious difference in cytotoxicity between the tumor cell lines was expected due to the different IC 50 values of SN‐38 in 251 and U87 cells (39.24 ng/mL for 251 cells and 294.3 ng/mL for U87 cells) . The PG1 fibers were cytotoxic to the 251 and U87 cells for at least 58 days, whereas the PG2 fibers were cytotoxic to the 251 and U87 cells for at least 72 days.…”

Section: Resultsmentioning

confidence: 98%

Anti-Neoplastic Cytotoxicity of SN-38-Loaded PCL/Gelatin Electrospun Composite Nanofiber Scaffolds against Human Glioblastoma Cells In Vitro

Zhu

Xia

et al. 2015

Journal of Pharmaceutical Sciences

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“…However, based upon the observed plasma concentrations of SN-38, the estimated concentration of SN-38 in the brain would be on the order of 10 nM if the tissue/plasma concentration ratio was similar to IN, which could not be measured by the analytical method used in this study. Further, others have suggested that SN-38 might be metabolized by glioma cells 39 . Thus, despite the low SN-38 concentrations in the brain, we conducted an efficacy study to see if enhanced IN delivery and perhaps intratumoral conversion of IN to SN-38 could slow tumor growth and improve survival.…”

Section: Discussionmentioning

confidence: 99%

Blood-brain barrier disruption and delivery of irinotecan in a rat model using a clinical transcranial MRI-guided focused ultrasound system

McDannold

Zhang²,

Supko

et al. 2020

Sci Rep

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We investigated controlled blood-brain barrier (BBB) disruption using a low-frequency clinical transcranial MRi-guided focused ultrasound (tcMRgfUS) device and evaluated enhanced delivery of irinotecan chemotherapy to the brain and a rat glioma model. Animals received three weekly sessions of FUS, FUS and 10 mg/kg irinotecan, or irinotecan alone. In each session, four volumetric sonications targeted 36 locations in one hemisphere. With feedback control based on recordings of acoustic emissions, 98% of the sonication targets (1045/1071) reached a pre-defined level of acoustic emission, while the probability of wideband emission (a signature for inertial cavitation) was than 1%. BBB disruption, evaluated by mapping the R1 relaxation rate after administration of an MRI contrast agent, was significantly higher in the sonicated hemisphere (P < 0.01). Histological evaluation found minimal tissue effects. Irinotecan concentrations in the brain were significantly higher (P < 0.001) with BBB disruption, but SN-38 was only detected in <50% of the samples and only with an excessive irinotecan dose. Irinotecan with BBB disruption did not impede tumor growth or increase survival. Overall these results demonstrate safe and controlled BBB disruption with a low-frequency clinical TcMRgFUS device. While irinotecan delivery to the brain was not neurotoxic, it did not improve outcomes in the F98 glioma model. Disrupting the blood-brain barrier (BBB) with focused ultrasound (FUS) and circulating microbubbles has been investigated to noninvasively and locally enhance drug delivery to the central nervous system 1. The method has been studied in numerous studies in animals 2-5 and has begun to be tested in humans to enhance chemotherapy delivery to brain tumors 6,7 and to reduce amyloid in Alzheimer's disease patients 8. While the exact mechanism of action is not fully understood, the disruption appears to arise via the mechanical interactions between the ultrasound field, the circulating microbubbles, and the vasculature that results in an opening of the BBB that lasts for several hours 9. FUS-induced BBB disruption has been shown to enable delivery of drugs, antibodies, nanoparticles, gene therapies, and even cells 10. Brain tumors do not have a fully-intact BBB. However, preclinical studies have shown that FUS can increase the permeability of the partially-intact blood-tumor barrier (BTB) and enhance the delivery of chemotherapy to CNS tumors 11-15. Perhaps more important is the prospect of getting drugs to surrounding areas where tumor cells are infiltrating into healthy brain where the BBB is intact. This infiltration, which often cannot be fully resected, leads to recurrence and is one of the main challenges in treating patients with brain tumors. BBB disruption is now being tested clinically 7,8,16. The ultrasound frequency used in clinical TcMRgFUS systems are lower than those used in most preclinical studies in rodents. A low frequency is used clinically to facilitate transmission through the thicker human skull. Reducing the ...

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Effective conversion of irinotecan to SN-38 after intratumoral drug delivery to an intracranial murine glioma model in vivo

Abstract: These results demonstrate that intratumorally administered CPT-11 can be effectively converted to SN-38 and this method of drug delivery is effective in extending the survival time of animals bearing malignant gliomas.

Cited by 19 publications

References 21 publications

A Preliminary Investigation into the Impact of a Pesticide Combination on Human Neuronal and Glial Cell Lines In Vitro

A Preliminary Investigation into the Impact of a Pesticide Combination on Human Neuronal and Glial Cell Lines In Vitro

Anti-Neoplastic Cytotoxicity of SN-38-Loaded PCL/Gelatin Electrospun Composite Nanofiber Scaffolds against Human Glioblastoma Cells In Vitro

Blood-brain barrier disruption and delivery of irinotecan in a rat model using a clinical transcranial MRI-guided focused ultrasound system

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