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Understanding the fundamental mechanisms involved in the induction of biological damage by ionizing radiation remains a major challenge of todays radiobiology research. The Monte Carlo simulation of physical, physicochemical and chemical processes involved may provide a powerful tool for the simulation of early damage induction. The Geant4-DNA extension of the general purpose Monte Carlo Geant4 simulation toolkit aims to provide the scientific community with an open source access platform for the mechanistic simulation of such early damage. This paper presents the most recent review of the Geant4-DNA extension, as available to Geant4 users since June 2015 (release 10.2 Beta). In particular, the review includes the description of new physical models for the description of electron elastic and inelastic interactions in liquid water, as well as new examples dedicated to the simulation of physicochemical and chemical stages of water radiolysis. Several implementations of geometrical models of biological targets are presented as well, and the list of Geant4-DNA examples is described.

ICTR-PHE 2012 Conference

Deregulation of apoptosis commonly occurs in melanoma cells and could be a reason for resistance. The effectiveness of different treatments depends on their ability to activate this process. In this study the effects of combined treatments with fotemustine (FM) and proton irradiation on the regulators of apoptosis were analyzed. Sub-confluent HTB140 human melanoma cells were treated with FM (100, 250 µM) 24 h prior to irradiation (12, 16 Gy). Cells were irradiated in the middle of the therapeutic 62 MeV proton spread out Bragg peak. Flow cytometric analysis of apoptosis and the Western blot analysis of apoptotic regulators were performed 6 or 48 h after treatments. Percent of apoptotic nuclei increased after applied treatments, reaching the level of 4 to 41 %. Induction of apoptosis was associated with p53 and Bax up regulation and Bcl-2 down regulation. The obtained results imply that analyzed treatments induce apoptosis through the activation of the mitochondrial apoptotic pathway, with better pro-apoptotic effects achieved by combined treatments.

Exposure to irradiation can trigger the p53 tumor suppressor to induce cell growth arrest or apoptosis. This study was conducted in order to evaluate the ability of carbon ions to induce apoptosis. The HTB140 melanoma cells were irradiated at three positions along the Bragg curve of the 62 MeV/u 12C ion beams. In this way the cells were exposed to different high linear energy transfer (LET) values. The percentage of apoptotic cells was evaluated by flow-cytometry and the corresponding apoptotic indexes were calculated. The expression of apoptosis-associated proteins, p53 and Bax was estimated by Western blot analyses. A dose dependent increase of apoptosis was noticed in all irradiation positions. When moving along the Bragg curve, i.e., with the raise of LET, the level of apoptosis increased, but was somewhat attenuated for the highest LET value. The corresponding apoptotic indexes ranged from 2.45 to 7.71. Moreover, the induction of apoptosis was associated with p53 and Bax up regulation

Joint Conference of the 33rd FEBS Congress/11th IUBMB Conference, Jun 28-Jul 03, 2008, Athens, Greece

Joint Conference of the 33rd FEBS Congress/11th IUBMB Conference, Jun 28-Jul 03, 2008, Athens, Greece

Malignant melanoma is a highly aggressive cancer with a poor prognosis due to resistance to radiotherapy and chemotherapy regimens. The mainstay of treatment remains DNA-alkylatingagent dacarbazine (DTIC). Fotemustine (FM), chloroethylnitrosourea agent, also has demonstrated significant antitumoral effects in malignantmelanoma. However, the resistance of melanoma cells limits their clinical application. In order to enhance the inhibition of melanoma cell growth, in this study, combined treatment of FM and DTIC with proton irradiation, was investigated. We analyzed the effects of combined treatment on HTB140 melanoma cell viability and proliferation. Significant inhibition of cell growth, especially cell proliferation, was obtained after treatment with protons and FM compare to single irradiation or drug treatment. Treatment with protons and DTIC has shown improved growth inhibition compare to appropriate single drug treatment, but not compare to irradiation as a single treatment. Physical chemistry 2006 : 8th international conference on fundamental and applied aspects of physical chemistry; Belgrade (Serbia); 26-29 September 2006

Human HTB140 melanoma cells were used to investigate different responses to single irradiation with protons, regarding cell proliferation, induction of apoptosis and expression of p53. Exponentially growing cells were irradiated close to the Bragg peak maximum of the unmodulated 62 MeV proton beam. Doses applied ranged from 8 to 24 Gy at the dose rate of 15 Gy/min. Cell proliferation, measured 6 and 48 h postirradiation, has shown highly significant dose and time dependent decrease. Protons induced apoptosis, 6 and 48 h after irradiation, decreasing with the increase of postirradiation incubation time. The largest number of apoptotic cells was at 6 h after irradiation with 16 Gy protons. High level of p53 expression was detected in all irradiated samples, as well as in controls and was independent of dose applied and postirradiation incubation time. Physical chemistry 2006 : 8th international conference on fundamental and applied aspects of physical chemistry; Belgrade (Serbia); 26-29 September 2006

Different experimental set-ups were designed to study cytotoxic and cytoststic effects on HTB140 melanoma cells after 1 h treatment with fotemustine (FM) or dacarbazine (DTIC). FM induced dose dependent cell inactivation, boosted by its toxicity, particularly for higher doses. DTIC treatment for 1 h was insufficient to provoke almost any effect on melanoma cells. Good correlation between viability and proliferation assays applied was detected for both drugs. Physical chemistry 2006 : 8th international conference on fundamental and applied aspects of physical chemistry; Belgrade (Serbia); 26-29 September 2006

The aim of this study was to investigate the in vitro effects of 8- chloroadenosine 3′, 5′-monophosphate (8-Cl-cAMP) and tiazofurin (TR) on the expression of c-myc gene in B16/F10 and B16/C3 mouse melanoma cells. Exponentially growing cells were treated with 8-Cl-cAMP or TR (5µmol - 25µmol) for 6h and 24h. The level of c-myc expression, estimated by RT-PCR, did not significantly change in B16/F10 cells after treatment with 8-Cl-cAMP or TR. Similar results were obtained in B16/C3 cells after treatment with 8-Cl-cAMP. The level of c-myc expression has shown a significant increase in B16/C3 cells after treatment with TR. Further studies of these agents will lead to better understanding of molecular mechanisms of their action. Physical chemistry 2004 : 7th international conference on fundamental and applied aspects of physical chemistry; Belgrade (Serbia); 21-23 September 2004