Dataset Information

Vascular effects of plinabulin (NPI-2358) and the influence on tumour response when given alone or combined with radiation.

ABSTRACT: This study investigated the anti-tumour effects of the novel vascular disrupting agent plinabulin (NPI-2358) when given alone or combined with radiation.Foot implanted C3H mammary carcinomas or leg implanted KHT sarcomas were used, with plinabulin injected intraperitoneally. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measurements were made with gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) on a 7-tesla magnet. Treatment response was assessed using regrowth delay (C3H tumours), clonogenic survival (KHT sarcomas) or histological estimates of necrosis for both models.Plinabulin (7.5 mg/kg) significantly reduced the initial area under curve (IAUC) and the transfer constant (K(trans)) within 1 hour after injection, reaching a nadir at 3 h, but returning to normal within 24 h. A dose-dependent decrease in IAUC and K(trans), was seen at 3 h. No significant anti-tumour effects were observed in the C3H tumours until doses of 12.5 mg/kg were achieved, but started at 1.5 mg/kg in the KHT sarcoma. Irradiating tumours 1 h after injecting plinabulin enhanced response in both models.Plinabulin induced a time- and dose-dependent decrease in tumour perfusion. The KHT sarcoma was more sensitive than the C3H tumour to the anti-tumour effects of plinabulin, while radiation response was enhanced in both models.

SUBMITTER: Bertelsen LB

PROVIDER: S-EPMC3509771 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Vascular effects of plinabulin (NPI-2358) and the influence on tumour response when given alone or combined with radiation.

Bertelsen Lotte B LB Shen Yuan Yuan YY Nielsen Thomas T Stødkilde-Jørgensen Hans H Lloyd G Kenneth GK Siemann Dietmar W DW Horsman Michael R MR

International journal of radiation biology 20111101 11

<h4>Purpose</h4>This study investigated the anti-tumour effects of the novel vascular disrupting agent plinabulin (NPI-2358) when given alone or combined with radiation.<h4>Materials and methods</h4>Foot implanted C3H mammary carcinomas or leg implanted KHT sarcomas were used, with plinabulin injected intraperitoneally. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measurements were made with gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) on a 7-tesla magnet. Treatment ...[more]

PMID: 21815749

Similar Datasets

Project description:High-dose radiotherapy effects are regulated by acute tumour endothelial cell death followed by rapid tumour cell death instead of canonical DNA break damage. Pre-treatment with ultrasound-stimulated microbubbles (USMB) has enabled higher-dose radiation effects with conventional radiation doses. This study aimed to confirm acute and longitudinal relationships between vascular shutdown and tumour cell death following radiation and USMB in a wild type murine fibrosarcoma model using in vivo imaging. Methods: Tumour xenografts were treated with single radiation doses of 2 or 8 Gy alone, or in combination with low-/high-concentration USMB. Vascular changes and tumour cell death were evaluated at 3, 24 and 72 h following therapy, using high-frequency 3D power Doppler and quantitative ultrasound spectroscopy (QUS) methods, respectively. Staining using in situ end labelling (ISEL) and cluster of differentiation 31 (CD31) of tumour sections were used to assess cell death and vascular distributions, respectively, as gold standard histological methods. Results: Results indicated a decrease in the power Doppler signal of up to 50%, and an increase of more than 5 dBr in cell-death linked QUS parameters at 24 h for tumours treated with combined USMB and radiotherapy. Power Doppler and quantitative ultrasound results were significantly correlated with CD31 and ISEL staining results (p < 0.05), respectively. Moreover, a relationship was found between ultrasound power Doppler and QUS results, as well as between micro-vascular densities (CD31) and the percentage of cell death (ISEL) (R2 0.5-0.9). Conclusions: This study demonstrated, for the first time, the link between acute vascular shutdown and acute tumour cell death using in vivo longitudinal imaging, contributing to the development of theoretical models that incorporate vascular effects in radiation therapy. Overall, this study paves the way for theranostic use of ultrasound in radiation oncology as a diagnostic modality to characterize vascular and tumour response effects simultaneously, as well as a therapeutic modality to complement radiation therapy.

Project description:Radiation therapy is currently utilised in the treatment of approximately 50% of cancer patients. A move towards patient tailored radiation therapy would help to improve the treatment outcome for patients as the inter-patient and intra-patient heterogeneity of cancer leads to large differences in treatment responses. In radiation therapy, a typical treatment outcome is cell cycle arrest which leads to cell cycle synchronisation. As treatment is typically given over multiple fractions it is important to understand how variation in the cell cycle can affect treatment response. Raman spectroscopy has previously been assessed as a method for monitoring radiation response in cancer cells and has shown promise in detecting the subtle biochemical changes following radiation exposure. This study evaluated Raman spectroscopy as a potential tool for monitoring cellular response to radiation in synchronised versus unsynchronised UVW human glioma cells in vitro. Specifically, it was hypothesised that the UVW cells would demonstrate a greater radiation resistance if the cell cycle phase of the cells was synchronised to the G1/S boundary prior to radiation exposure. Here we evaluated whether Raman spectroscopy, combined with cell cycle analysis and DNA damage and repair analysis (γ-H2AX assay), could discriminate the subtle cellular changes associated with radiation response. Raman spectroscopy combined with principal component analysis (PCA) was able to show the changes in radiation response over 24 hours following radiation exposure. Spectral changes were assigned to variations in protein, specifically changes in protein signals from amides as well as changes in lipid expression. A different response was observed between cells synchronised in the cell cycle and unsynchronised cells. After 24 hours following irradiation, the unsynchronised cells showed greater spectral changes compared to the synchronised cells demonstrating that the cell cycle plays an important role in the radiation resistance or sensitivity of the UVW cells, and that radiation resistance could be induced by controlling the cell cycle. One of the main aims of cancer treatment is to stop the proliferation of cells by controlling or halting progression through the cell cycle, thereby highlighting the importance of controlling the cell cycle when studying the effects of cancer treatments such as radiation therapy. Raman spectroscopy has been shown to be a useful tool for evaluating the changes in radiation response when the cell cycle phase is controlled and therefore highlighting its potential for assessing radiation response and resistance.

Project description:Tumour cells exhibit altered metabolic pathways that lead to radiation resistance and disease progression. Raman spectroscopy (RS) is a label-free optical modality that can monitor post-irradiation biomolecular signatures in tumour cells and tissues. Convolutional Neural Networks (CNN) perform automated feature extraction directly from data, with classification accuracy exceeding that of traditional machine learning, in cases where data is abundant and feature extraction is challenging. We are interested in developing a CNN-based predictive model to characterize clinical tumour response to radiation therapy based on their degree of radiosensitivity or radioresistance. In this work, a CNN architecture is built for identifying post-irradiation spectral changes in Raman spectra of tumour tissue. The model was trained to classify irradiated versus non-irradiated tissue using Raman spectra of breast tumour xenografts. The CNN effectively classified the tissue spectra, with accuracies exceeding 92.1% for data collected 3 days post-irradiation, and 85.0% at day 1 post-irradiation. Furthermore, the CNN was evaluated using a leave-one-out- (mouse, section or Raman map) validation approach to investigate its generalization to new test subjects. The CNN retained good predictive accuracy (average accuracies 83.7%, 91.4%, and 92.7%, respectively) when little to no information for a specific subject was given during training. Finally, the classification performance of the CNN was compared to that of a previously developed model based on group and basis restricted non-negative matrix factorization and random forest (GBR-NMF-RF) classification. We found that CNN yielded higher classification accuracy, sensitivity, and specificity in mice assessed 3 days post-irradiation, as compared with the GBR-NMF-RF approach. Overall, the CNN can detect biochemical spectral changes in tumour tissue at an early time point following irradiation, without the need for previous manual feature extraction. This study lays the foundation for developing a predictive framework for patient radiation response monitoring.

Dataset Information

Vascular effects of plinabulin (NPI-2358) and the influence on tumour response when given alone or combined with radiation.

Publications

Vascular effects of plinabulin (NPI-2358) and the influence on tumour response when given alone or combined with radiation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets