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Strategies to Enhance Radiosensitivity to Heavy Ion Radiation Therapy.

ABSTRACT: Heavy ion radiation therapy has been increasingly used due to several advantages over low linear energy transfer (LET) photon therapy, but further improvement of its therapeutic efficacy would be necessary. In this review, we summarize effective radiosensitizers for heavy ion radiation therapy and mechanisms associated with the radiosensitization. High LET heavy ions induce more complex and clustered DNA damage than low LET radiation. Inhibition of homologous recombimation repair or nonhomologous end rejoining and dysfunctional cell cycle checkpoint have been reported to sensitize cancer cells to heavy ions. Radiosenstizing agents, including DNA damage response inhibitors, Hsp90 inhibitors, histone acetylase inhibitors, and nanomaterials have been found to enhance cell killing by heavy ion irradiation through disrupted DNA damage response, cell cycle arrest, or other cellular processes. The use of these radiosensitizers could be a promising strategy to enhance the efficacy of heavy ion radiation therapy.

SUBMITTER: Lee Y

PROVIDER: S-EPMC6871583 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Strategies to Enhance Radiosensitivity to Heavy Ion Radiation Therapy.

Lee Younghyun Y Okayasu Ryuichi R

International journal of particle therapy 20180921 1

Heavy ion radiation therapy has been increasingly used due to several advantages over low linear energy transfer (LET) photon therapy, but further improvement of its therapeutic efficacy would be necessary. In this review, we summarize effective radiosensitizers for heavy ion radiation therapy and mechanisms associated with the radiosensitization. High LET heavy ions induce more complex and clustered DNA damage than low LET radiation. Inhibition of homologous recombimation repair or nonhomologou ...[more]

PMID: 31773023

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Project description:BackgroundThe objective of this study was to evaluate the outcomes of patients with high-grade glioma who received treatment with particle radiotherapy.MethodsBetween June 2015 and October 2018, 50 consecutive and nonselected patients with glioblastoma multiforme (n = 34) or anaplastic glioma (n = 16) were treated at the Shanghai Proton and Heavy Ion Center. Twenty-four patients received proton radiotherapy (at a dose of 60 gray-equivalents in 30 daily fractions), and 26 patients received proton radiotherapy plus a carbon-ion radiotherapy (CIRT) boost in various dose-escalating schemes. All patients received temozolomide because of their age or their O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Progression-free survival (PFS) and overall survival (OS) rates, as well as treatment-induced toxicities, were analyzed.ResultsAt a median follow-up of 14.3 months (range, 4.8-39.6 months), the 12-month and 18-month OS rates were 87.8% (95% CI, 77.6%-98.0%) and 72.8% (95% CI, 56.7%-88.9%), respectively, and the 12-month and 18-month PFS rates were 74.2% (95% CI, 60.9%-87.5%) and 59.8% (95% CI, 43.1%-76.5%), respectively. Univariate analyses revealed that age (>50 vs ≤50 years), World Health Organization grade (3 vs 4), and Karnofsky performance status (>80 vs ≤80) were significant prognosticators for OS, and IDH mutation and World Health Organization grade were significant for predicting PFS. Furthermore, MGMT promoter methylation, performance status, and age showed a trend toward predicting PFS. No significant predictive factors for PFS or OS were identified in multivariate analyses. Twenty-nine patients experienced grade 1 treatment-related acute adverse effects, and 11 developed grade 1 (n = 6) or grade 2 (n = 5) late adverse effect of radiation-induced brain necrosis. No grade 3, 4, or 5 toxicities were observed.ConclusionsParticle radiotherapy produced 18-month OS and PFS rates of 72.8% and 59.8%, respectively, with acceptable adverse effects in patients with high-grade glioma. Particle radiotherapy at a dose ≥60 gray-equivalents appears to be safe and potentially effective.

Project description:BackgroundRadiation therapy is a main treatment option for cancer. Due to normal tissue toxicity, radiosensitizers are commonly used to enhance RT. In particular, heavy metal or high-Z materials, such as gold nanoparticles, have been investigated as radiosensitizers. So far, however, the related studies have been focused on spherical gold nanoparticles. In this study, we assessed the potential of ultra-thin gold nanowires as a radiosensitizer, which is the first time.MethodsGold nanowires were synthesized by the reduction of HAuCl4 in hexane. The as-synthesized gold nanowires were then coated with a layer of PEGylated phospholipid to be rendered soluble in water. Spherical gold nanoparticles coated with the same phospholipid were also synthesized as a comparison. Gold nanowires and gold nanospheres were first tested in solutions for their ability to enhance radical production under irradiation. They were then incubated with 4T1 cells to assess whether they could elevate cell oxidative stress under irradiation. Lastly, gold nanowires and gold nanoparticles were intratumorally injected into a 4T1 xenograft model, followed by irradiation applied to tumors (3 Gy/per day for three days). Tumor growth was monitored and compared.ResultsOur studies showed that gold nanowires are superior to gold nanospheres in enhancing radical production under X-ray radiation. In vitro analysis found that the presence of gold nanowires caused elevated lipid peroxidation and intracellular oxidative stress under radiation. When tested in vivo, gold nanowires plus irradiation led to better tumor suppression than gold nanospheres plus radiation. Moreover, gold nanowires were found to be gradually reduced to shorter nanowires by glutathione, which may benefit fractionated radiation.ConclusionOur studies suggest that gold nanowires are a promising type of radiosensitizer that can be safely injected into tumors to enhance radiotherapy. While the current study was conducted in a breast cancer model, the approach can be extended to the treatment of other cancer types.

Project description:BackgroundThis study investigated the effectiveness and underpinning mechanisms of radiosensitization using octaarginine (R8)-modified gold nanoparticle-poly(ethylene glycol) (GNP-PEG-R8) in colorectal cancer cell line LS180 to megavoltage radiotherapy in vitro.MethodIn-house synthesized GNP-PEG was characterized by transmission electron microscopy, dynamic light scattering, ultraviolet-visible spectrophotometry, and X-ray photoelectron spectroscopy. Inductively coupled plasma mass spectroscopy was used to quantify internalization. Direct cytotoxicity was established using the Cell Counting Kit-8, while radiosensitivity was determined using the gold standard in vitro clonogenic assay. Cell-cycle distribution, apoptosis, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were analyzed by flow cytometry, further exploring the key mechanisms driving GNP-PEG-R8 radiosensitization.ResultsThe core GNP diameter was 6.3±1.1 nm (mean±SD). Following functionalization, the hydrodynamic diameter increased to 19.7±2.8 nm and 27.8±1.8 nm for GNP-PEG and GNP-PEG-R8, with respective surface plasmon resonance peaks of 515 nm and 525 nm. Furthermore, incorporation of the R8 significantly increased nanoparticle internalization compared to GNP-PEG (p<0.001) over a 1 h treatment period. Functionalized GNPs confer little cytotoxicity below 400 nM. In clonogenic assays, radiation combined with GNP-PEG-R8 induced a significant reduction in colony formation compared with radiation alone, generating a sensitizer enhancement ratio of 1.59. Furthermore, GNP-PEG-R8 plus radiation predominantly induced cell-cycle arrest in the G2/M phase, increasing G2/M stalling by an additional 10% over GNP-PEG, markedly promoting apoptosis (p<0.001). Finally, ROS levels and alterations in MMP were investigated, indicating a highly significant (p<0.001) change in both parameters following the combined treatment of GNP-PEG-R8 and radiation over radiation alone.ConclusionR8-modified GNPs were efficiently internalized by LS180 cells, exhibiting minimal cytotoxicity. This yielded significant radiosensitization in response to megavoltage radiation. GNP-PEG-R8 may enhance radiosensitivity by arresting cell cycle and inducing apoptosis, with elevated ROS identified as the likely initiator.

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Strategies to Enhance Radiosensitivity to Heavy Ion Radiation Therapy.

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Strategies to Enhance Radiosensitivity to Heavy Ion Radiation Therapy.

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