Combined temozolomide and sunitinib treatment leads to better tumour control but increased vascular resistance in O6-methylguanine methyltransferase-methylated gliomas

Czabanka, Marcus; Bruenner, Jeanette; Parmaksiz, Güliz; Broggini, Thomas; Topalovic, Miroslav; Bayerl, Simon; Auf, Gregor; Kremenetskaia, Irina; Nieminen, M.; Jabouille, Arnaud; Mueller, Susanne; Harms, Ulrike; Harms, Christoph; Koch, Arend; Heppner, Frank L.; Vajkoczy, Peter

doi:10.1016/j.ejca.2013.02.019

Cited by 19 publications

(22 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Combining the chemotherapeutic agent, topotecan, with pazopanib significantly inhibited tumor growth, despite an increase in the number of vessels that were infiltrated by pericytes (271). Similar results were observed in a preclinical malignant glioma model following treatment with the combination of temozolomide and sunitinib (272).…”

Section: Recruitment Of Pericytessupporting

confidence: 67%

Resistance Mechanisms to Anti-angiogenic Therapies in Cancer

et al. 2020

View full text Add to dashboard Cite

Section: Recruitment Of Pericytessupporting

confidence: 67%

Resistance Mechanisms to Anti-angiogenic Therapies in Cancer

et al. 2020

View full text Add to dashboard Cite

“…These results are similar to the results of combination therapy involving TMZ and SU with U87 cells inserted into mice. a synergistic effect of TMZ and SU was observed when they were applied together, compared with the case where only TMZ was applied [39]. Therefore, the results observed in this microenvironmental tissue are analogous to the in vivo results.…”

Section: Effects Of Tmz and Su On Vascularized Mctsssupporting

confidence: 67%

3D Bioprinted Vascularized Tumour for Drug Testing

Han

Kim

Chen

et al. 2020

IJMS

View full text Add to dashboard Cite

An in vitro screening system for anti-cancer drugs cannot exactly reflect the efficacy of drugs in vivo, without mimicking the tumour microenvironment (TME), which comprises cancer cells interacting with blood vessels and fibroblasts. Additionally, the tumour size should be controlled to obtain reliable and quantitative drug responses. Herein, we report a bioprinting method for recapitulating the TME with a controllable spheroid size. The TME was constructed by printing a blood vessel layer consisting of fibroblasts and endothelial cells in gelatine, alginate, and fibrinogen, followed by seeding multicellular tumour spheroids (MCTSs) of glioblastoma cells (U87 MG) onto the blood vessel layer. Under MCTSs, sprouts of blood vessels were generated and surrounding MCTSs thereby increasing the spheroid size. The combined treatment involving the anti-cancer drug temozolomide (TMZ) and the angiogenic inhibitor sunitinib was more effective than TMZ alone for MCTSs surrounded by blood vessels, which indicates the feasibility of the TME for in vitro testing of drug efficacy. These results suggest that the bioprinted vascularized tumour is highly useful for understanding tumour biology, as well as for in vitro drug testing.

show abstract

“…A recent study showed that sequential application of temozolomide and sunitinib does not enhance antitumor efficacy compared to single agent therapy, whereas a combinatory application of both drugs was potent on tumor volume. 58 Altogether, these findings indicate that sunitinib can be combined with cytotoxic drugs such as alkylating agents to reinforce antitumor efficacy.…”

Section: Discussionmentioning

confidence: 97%

Sunitinib impedes brain tumor progression and reduces tumor‐induced neurodegeneration in the microenvironment

et al. 2015

View full text Add to dashboard Cite

Malignant gliomas can be counted to the most devastating tumors in humans. Novel therapies do not achieve significant prolonged survival rates. The cancer cells have an impact on the surrounding vital tissue and form tumor zones, which make up the tumor microenvironment. We investigated the effects of sunitinib, a small molecule multitargeted receptor tyrosine kinase inhibitor, on constituents of the tumor microenvironment such as gliomas, astrocytes, endothelial cells, and neurons. Sunitinib has a known anti-angiogenic effect. We found that sunitinib normalizes the aberrant tumor-derived vasculature and reduces tumor vessel pathologies (i.e. auto-loops). Sunitinib has only minor effects on the normal, physiological, non-proliferating vasculature. We found that neurons and astrocytes are protected by sunitinib against glutamate-induced cell death, whereas sunitinib acts as a toxin towards proliferating endothelial cells and tumor vessels. Moreover, sunitinib is effective in inducing glioma cell death. We determined the underlying pathways by which sunitinib operates as a toxin on gliomas and found vascular endothelial growth factor receptor 2 (VEGFR2, KDR/Flk1) as the main target to execute gliomatoxicity. The apoptosis-inducing effect of sunitinib can be mimicked by inhibition of VEGFR2. Knockdown of VEGFR2 can, in part, foster the resistance of glioma cells to receptor tyrosine kinase inhibitors. Furthermore, sunitinib alleviates tumor-induced neurodegeneration. Hence, we tested whether temozolomide treatment could be potentiated by sunitinib application. Here we show that sunitinib can amplify the effects of temozolomide in glioma cells. Thus, our data indicate that combined treatment with temozolomide does not abrogate the effects of sunitinib. In conclusion, we found that sunitinib acts as a gliomatoxic agent and at the same time carries out neuroprotective effects, reducing tumor-induced neurodegeneration. Thus, this report uncovered sunitinib's actions on the brain tumor microenvironment, revealing novel aspects for adjuvant approaches and new clinical assessment criteria when applied to brain tumor patients.

show abstract

Combined temozolomide and sunitinib treatment leads to better tumour control but increased vascular resistance in O6-methylguanine methyltransferase-methylated gliomas

Cited by 19 publications

References 26 publications

Resistance Mechanisms to Anti-angiogenic Therapies in Cancer

Resistance Mechanisms to Anti-angiogenic Therapies in Cancer

3D Bioprinted Vascularized Tumour for Drug Testing

Sunitinib impedes brain tumor progression and reduces tumor‐induced neurodegeneration in the microenvironment

Contact Info

Product

Resources

About