A New Model for Prediction of Drug Distribution in Tumor and Normal Tissues: Pharmacokinetics of Temozolomide in Glioma Patients

Rosso, Lula; Brock, Cathryn; Gallo, James M.; Saleem, Azeem; Price, Patricia M; Turkheimer, Federico; Aboagye, Eric O.

doi:10.1158/0008-5472.can-08-2356

Cited by 143 publications

(111 citation statements)

References 26 publications

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“…Thus, there is no need for intratumoral delivery, resulting in easier drug administration. We have no direct evidence that the drug crosses the BBB; however, the brain regions around the tumors, where tumor expansion occurs does have an intact BBB (34,35), suggesting that NEO212 may cross the BBB.…”

Section: Discussionmentioning

confidence: 82%

NEO212, Temozolomide Conjugated to Perillyl Alcohol, Is a Novel Drug for Effective Treatment of a Broad Range of Temozolomide-Resistant Gliomas

Cho¹,

Wang²,

Jhaveri³

et al. 2014

Molecular Cancer Therapeutics

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Patients with glioblastoma multiforme (GBM), a malignant primary brain tumor, inevitably develop resistance to standard-of-care chemotherapy, temozolomide. This study explores the effects of the novel agent NEO212, a conjugate of temozolomide to perillyl alcohol, on temozolomide-resistant gliomas. NEO212 was tested for cytotoxic activity on three human temozolomide-resistant glioma cell lines, which were resistant to temozolomide based on overexpression of the base excision repair (BER) pathway, mismatch repair (MMR) deficiency, or overexpression of O 6 methyl-guanine-DNA methyltransferase (MGMT). BER expression was evaluated by Western blotting and PARP activity. MMR deficiency was determined by Western blotting and microsatellite instability. MGMT overexpression was evaluated by Western blotting and O 6 -benzylguanine (O 6 BG) inhibition. For in vivo evaluation of NEO212, temozolomide-resistant glioma cells were implanted into immune-incompetent mice, and NEO212 was administered. NEO212, at equimolar concentrations of temozolomide, was more cytotoxic for temozolomideresistant cells than temozolomide and not toxic to normal cells. NEO212-induced cell death in temozolomide-resistant glioma cells was independent of such mechanisms of resistance as high levels of MGMT, MMR deficiencies, or overexpression of BER proteins. NEO212 functions as a DNA alkylating agent, similar to temozolomide; however, this novel conjugate is unique for it may induce endoplasmic reticulum (ER) stress and inhibits autophagy. In vivo studies show that NEO212 reduces intracranial tumor growth and increases animal survival without significant toxicity. These results demonstrate that NEO212 is an effective drug against malignant gliomas that can be used for a broad range of newly diagnosed and temozolomide-resistant gliomas.

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Section: Discussionmentioning

confidence: 82%

NEO212, Temozolomide Conjugated to Perillyl Alcohol, Is a Novel Drug for Effective Treatment of a Broad Range of Temozolomide-Resistant Gliomas

Cho¹,

Wang²,

Jhaveri³

et al. 2014

Molecular Cancer Therapeutics

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“…The clinically relevant regimen for TMZ consists of 150-200 mg/m 2 /day, via oral administration, on days 1-5 of a 28-day cycle. 1 However, its peak concentration measured is only 50 mmol/l in patient's blood samples [9][10][11][12] and 5 mmol/l in the CSF. 12 Thus, it has been proposed that the intratumoral concentration may not exceed 50 mmol/l.…”

Section: Resultsmentioning

confidence: 96%

Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy

et al. 2014

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Glioblastoma multiforme patients have a poor prognosis due to therapeutic resistance and tumor relapse. It has been suggested that gliomas are driven by a rare subset of tumor cells known as glioma stem cells (GSCs). This hypothesis states that only a few GSCs are able to divide, differentiate, and initiate a new tumor. It has also been shown that this subpopulation is more resistant to conventional therapies than its differentiated counterpart. In order to understand glioma recurrence post therapy, we investigated the behavior of GSCs after primary chemotherapy. We first show that exposure of patient-derived as well as established glioma cell lines to therapeutic doses of temozolomide (TMZ), the most commonly used antiglioma chemotherapy, consistently increases the GSC pool over time both in vitro and in vivo. Secondly, lineage-tracing analysis of the expanded GSC pool suggests that such amplification is a result of a phenotypic shift in the non-GSC population to a GSC-like state in the presence of TMZ. The newly converted GSC population expresses markers associated with pluripotency and stemness, such as CD133, SOX2, Oct4, and Nestin. Furthermore, we show that intracranial implantation of the newly converted GSCs in nude mice results in a more efficient grafting and invasive phenotype. Taken together, these findings provide the first evidence that glioma cells exposed to chemotherapeutic agents are able to interconvert between non-GSCs and GSCs, thereby replenishing the original tumor population, leading to a more infiltrative phenotype and enhanced chemoresistance. This may represent a potential mechanism for therapeutic relapse.

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“…Thus, the angiogenic and fenestrated tumor vasculature present in high-grade gliomas may result in higher drug concentrations in the tumor than those found in healthy brain tissue. This phenomenon has been demonstrated for temozolomide and methotrexate not only in rodents but also in humans (de Lange et al, 1995;Blakeley et al, 2009;Rosso et al, 2009). Because it is a highly polar molecule, GCV (Table 1) would be placed in the category of a drug with poor permeability across biologic membranes, and the GCV concentration in tumor likely exceeds the concentration in healthy brain.…”

Section: Introductionmentioning

confidence: 78%

Brain Pharmacokinetics of Ganciclovir in Rats with Orthotopic BT4C Glioma

Gynther

Kääriäinen

Hakkarainen

et al. 2015

Drug Metabolism and Disposition

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Ganciclovir (GCV) is an essential part of the Herpes simplex virus thymidine kinase (HSV-tk) gene therapy of malignant gliomas. The purpose of this study was to investigate the brain pharmacokinetics and tumor uptake of GCV in the BT4C rat glioma model. GCV's brain and tumor uptakes were investigated by in vivo microdialysis in rats with orthotopic BT4C glioma. In addition, the ability of GCV to cross the blood-brain barrier and tumor vasculature was assessed with in situ rat brain perfusion. Finally, the extent to which GCV could permeate across the BT4C glioma cell membrane was assessed in vitro. The areas under the concentration curve of unbound GCV in blood, brain extracellular fluid (ECF), and tumor ECF were 6157, 1658, and 4834 mM×min, respectively. The apparent maximum unbound concentrations achieved within 60 minutes were 46.9, 11.8, and 25.8 mM in blood, brain, and tumor, respectively. The unbound GCV concentrations in brain and tumor after in situ rat brain perfusion were 0.41 and 1.39 nmol/g, respectively. The highly polar GCV likely crosses the fenestrated tumor vasculature by paracellular diffusion. Thus, GCV is able to reach the extracellular space around the tumor at higher concentrations than that in healthy brain. However, GCV uptake into BT4C cells at 100 mM was only 2.1 pmol/mg of protein, and no active transporter-mediated disposition of GCV could be detected in vitro. In conclusion, the limited efficacy of HSV-tk/GCV gene therapy may be due to the poor cellular uptake and rapid elimination of GCV.

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A New Model for Prediction of Drug Distribution in Tumor and Normal Tissues: Pharmacokinetics of Temozolomide in Glioma Patients

Cited by 143 publications

References 26 publications

NEO212, Temozolomide Conjugated to Perillyl Alcohol, Is a Novel Drug for Effective Treatment of a Broad Range of Temozolomide-Resistant Gliomas

NEO212, Temozolomide Conjugated to Perillyl Alcohol, Is a Novel Drug for Effective Treatment of a Broad Range of Temozolomide-Resistant Gliomas

Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy

Brain Pharmacokinetics of Ganciclovir in Rats with Orthotopic BT4C Glioma

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