Gefitinib accumulation in glioblastoma tissue

Höfer, Silvia; Frei, Karl; Rutz, Hans

doi:10.4161/cbt.5.5.2653

Cited by 20 publications

(16 citation statements)

References 38 publications

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“…GBM patients with a relapse, however in good performance status are offered secondary surgery where appropriate and participation in a prospective trial with gefitinib [1]. Gefitinib is currently under scrutiny for the treatment of high grade glioma [2].…”

mentioning

confidence: 99%

Gefitinib concentrations in human glioblastoma tissue

Höfer

Frei

2006

J Neurooncol

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confidence: 99%

Gefitinib concentrations in human glioblastoma tissue

Höfer

Frei

2006

J Neurooncol

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“…The observed penetration of gefitinib through BBB may likely be the consequences of the altered BBB integrity as a result of intracranial tumors and/or prior exposures to chemotherapy. This speculation is supported by a study conducted by Hofer et al [68] showing a 10-13-fold higher gefitinib concentrations in the GBM tissues than in plasma from two patients receiving gefitinib treatments and prior first-line chemotherapy. The reasonable extent of gefitinib accumulation in GBM tissues may also be due to the fact that CYP3A, the key cytochrome P450 enzyme that metabolizes gefitinib [56], is expressed at a low level in GBM tissues [68].…”

Section: Gefitinibmentioning

confidence: 78%

“…This speculation is supported by a study conducted by Hofer et al [68] showing a 10-13-fold higher gefitinib concentrations in the GBM tissues than in plasma from two patients receiving gefitinib treatments and prior first-line chemotherapy. The reasonable extent of gefitinib accumulation in GBM tissues may also be due to the fact that CYP3A, the key cytochrome P450 enzyme that metabolizes gefitinib [56], is expressed at a low level in GBM tissues [68]. Conversely, enzyme-inducing antiepileptic drugs (EIAEDs) induce CYP3A and Reardon et al [51] reported that GBM exposure to gefitinib was significantly lowered by the concurrent use of EIAEDs.…”

Section: Gefitinibmentioning

confidence: 78%

EGFR-Targeted Therapy in Malignant Glioma: Novel Aspects and Mechanisms of Drug Resistance

Lo¹

2010

CMP

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Glioblastoma, GBM, is the most frequent brain malignancy in adults. Patients with these tumors survive only, approximately, one year after diagnosis and rarely survive beyond two years. This poor prognosis is, in part, due to our insufficient understanding of the complex aggressive nature of these tumors and the lack of effective therapy. In GBM, over-expression of EGFR and/or its constitutively activated variant EGFRvIII is a major characteristic and is associated with tumorigenesis and more aggressive phenotypes, such as, invasiveness and therapeutic resistance. Consequently, both have been major targets for GBM therapy, however, clinical trials of EGFRand EGFRvIII-targeted therapies have yielded unsatisfactory results and the molecular basis for the poor results is still unclear. Thus, in this review, we will summarize results of recent clinical trials and recent advances made in the understanding of the EGFR/EGFRvIII pathways with a key focus on those associated with intrinsic resistance of GBM to EGFR-targeted therapy. For example, emerging evidence indicates an important role that PTEN plays in predicting GBM response to EGFR-targeted therapy. Aberrant Akt/mTOR pathway has been shown to contribute to the resistant phenotype. Also, several studies have reported that EGFR/EGFRvIII's cross-talk with the oncogenic transcription factorSTAT3 and receptor tyrosine kinases, (c-Met and PDGFR) potentially lead to GBM resistance to anti-EGFR therapy. Other emerging mechanisms, including one involving HMG-CoA reductase, will also be discussed in this mini-review. These recent findings have provided new insight into the highly complex and interactive nature of the EGFR pathway and generated rationales for novel combinational targeted therapies for these tumors.

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“…Given that there are fewer concerns with regard to delivery of TKIs to the site of GBM when compared with antibodies, the development of these reagents for the treatment of GBM is more advanced. In fact, excellent targeting of these agents to the site of GBM has been well demonstrated (Hofer et al, 2006;Hegi et al, 2011).…”

Section: Tyrosine Kinase Inhibitors That Target the Egfrmentioning

confidence: 99%

Advances in the Development of EGFR Targeted Therapies for the Treatment of Glioblastoma

Johns¹

2012

Novel Therapeutic Concepts in Targeting Glioma

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Gefitinib accumulation in glioblastoma tissue

Cited by 20 publications

References 38 publications

Gefitinib concentrations in human glioblastoma tissue

Gefitinib concentrations in human glioblastoma tissue

EGFR-Targeted Therapy in Malignant Glioma: Novel Aspects and Mechanisms of Drug Resistance

Advances in the Development of EGFR Targeted Therapies for the Treatment of Glioblastoma

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