Impact of Stromal Sensitivity on Radiation Response of Tumors

Background and Purpose The causes of tumor response variation to radiation remain obscure, thus hampering the development of predictive assays and strategies to decrease resistance. The present study evaluates the impact of host tumor stromal elements and the in vivo environment on tumor cell kill, and relationship between tumor cell radiosensitivity and the tumor control dose. Material and Methods Five endpoints were evaluated and compared in a radiosensitive DNA double-strand break repair-defective (DNA-Pkcs−/−) tumor line, and its DNA-PKcs repair competent transfected counterpart. In vitro colony formation assays were performed on in vitro cultured cells; on cells obtained directly from tumors, and on cells irradiated in situ. Permanent local control was assessed by the TCD50 assay. Vascular effects were evaluated by functional vascular density assays. Results The fraction of repair competent and repair deficient tumor cells surviving radiation did not substantially differ whether irradiated in vitro, i.e., in the absence of host stromal elements and factors, from the fraction of cells killed following in vivo irradiation. Additionally, the altered tumor cell sensitivity resulted in a proportional change in the dose required to achieve permanent local control. The estimated number of tumor cells per tumor, their cloning efficiency and radiosensitivity, all assessed by in vitro assays, were used to predict successfully, the measured tumor control doses. Conclusion The number of clonogens per tumor and their radiosensitivity govern the permanent local control dose.

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“…This contrasts with studies indicating that the radiation sensitivity of the tumor cells is the primary determinant of response [9–12]. …”

Section: Introductioncontrasting

confidence: 63%

Determinates of tumor response to radiation: Tumor cells, tumor stroma and permanent local control

Huang

Chen

et al. 2014

Radiotherapy and Oncology

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“…While previous studies in animal tumor models have suggested that tumor microvascular damage yields no critical contribution to tumor cure by radiation [1–3], genetic and pre-clinical studies in our laboratory found disruption of tumor vasculature obligate for cure with SDRT at exposures exceeding 10 Gy [4–6]. This endothelial cell dysfunction results from activation of acid sphingomyelinase (ASMase), converting sphingomyelin to the second messenger ceramide in the endothelial plasma membrane.…”

mentioning

confidence: 84%

Axitinib sensitization of high Single Dose Radiotherapy

Rao

Thompson

Cheng

et al. 2014

Radiotherapy and Oncology

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Background and purpose Single Dose Radiation Therapy (SDRT) provides remarkably high rates of control even for tumors resistant to fractionated radiotherapy. SDRT tumor control depends on acute acid sphingomyelinase-mediated endothelial cell injury and monoclonal antibodies targeting Vascular Endothelial Cell Growth Factor (VEGF) signaling radiosensitized tumor endothelium when delivered immediately prior to irradiation. Here we evaluate the ability of the oral VEGF receptor inhibitor, axitinib, to sensitize tumor endothelium and increase tumor control with SDRT. Methods and materials Axitinib was added to primary cultured endothelial cells, or administered orally to Sv129/BL6 mice bearing radiosensitive MCA/129 sarcoma or radioresistant B16F1 melanoma flank tumors, followed by SDRT. Endothelial apoptosis was assessed by TUNEL assay or bis-benzamide staining. Mice with irradiated tumors were followed for 90 days to evaluate the impact of axitinib on SDRT tumor control. Results Pre-treatment with axitinib increased acute endothelial cell apoptosis following SDRT in vitro, and in vivo for both MCA/129 and B16F1 tumors. Axitinib correspondingly increased SDRT tumor growth delay and complete response rate (by 40%) for both tumors. Administration precisely 1 h before SDRT was critical for radiosensitization. Conclusions Axitinib radiosensitizes tumor endothelial cells and enhances tumor cure with SDRT, which may permit dose de-escalation and significantly expand the range of clinical indications for SDRT.

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“…The primary cultures were established directly from the mouse embryos obtained from the Edwin L Steele Laboratory, Massachusetts General Hospital, as described previously (46). These cells were cultured in Dulbecco's modified Eagle's medium at 37°C in humidified air with 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

The Ability of p53 to Activate Downstream Genes p21 and MDM2, and Cell Cycle Arrest following DNA Damage Is Delayed and Attenuated in scid Cells Deficient in the DNA-dependent Protein Kinase

Kachnic

Wunsch

et al. 1999

Journal of Biological Chemistry

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scid mouse embryonic fibroblasts are deficient in DNAdependent protein kinase activity due to a mutation in the C-terminal domain of the catalytic subunit (DNAPKcs). When exposed to ionizing radiation, the increase in levels of p53 was the same as in normal mouse embryonic fibroblasts. However, the rise in p21 WAF1/cip1 and mdm2 was found to be delayed and attenuated, which correlated in time with delayed onset of G 1 /S arrest by flow cytometric analysis. The p53-dependent G 1 checkpoint was not eliminated: inactivation of p53 by the E6 protein in scid cells resulted in the complete loss of detectable G 1 /S arrest after DNA damage. Immunofluorescence analysis of normal cells revealed p53 to be localized predominantly within the cytoplasm prior to irradiation and then translocate to the nucleus after irradiation. In contrast, scid cells show abnormal accumulation of p53 in the nucleus independent of irradiation, which was confirmed by immunoblot analysis of nuclear lysates. Taken together, these data suggest that loss of DNA-PK activity appears to attenuate the kinetics of p53 to activate downstream genes, implying that DNA-PK plays a role in post-translational modification of p53, without affecting the increase in levels of p53 in response to DNA damage.

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Impact of Stromal Sensitivity on Radiation Response of Tumors

Cited by 68 publications

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Determinates of tumor response to radiation: Tumor cells, tumor stroma and permanent local control

Determinates of tumor response to radiation: Tumor cells, tumor stroma and permanent local control

Axitinib sensitization of high Single Dose Radiotherapy

The Ability of p53 to Activate Downstream Genes p21 and MDM2, and Cell Cycle Arrest following DNA Damage Is Delayed and Attenuated in scid Cells Deficient in the DNA-dependent Protein Kinase

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