Quantitative analysis of the effects of iododeoxyuridine and ionising radiation treatment on the cell cycle dynamics of DNA mismatch repair deficient human colorectal cancer cells

In this study, we quantitatively analyze the mechanism by which androgen deprivation therapy (ADT) is enhancing radiosensitivity in prostate cancer (PCa) patients. It has been shown in laboratory experiments, as well as in patient data in the literature, that the androgen receptor (AR) reduces the effectiveness of ionizing radiation treatment by enhancing the non-homologous end joining (NHEJ) repair of radiation damage. The suppression of AR by ADT suppresses the activity of NHEJ that leads to radiosensitivity in PCa patients. In this paper, we have studied this positive interaction between AR and NHEJ using mathematical models of the NHEJ that we have developed using both the experimental and clinical data for PCa. Our results show that the biological observation of suppression of AR by ADT leading to down-regulation of the first NHEJ protein Ku and NHEJ is a plausible biological mechanism that explains both the experimental and clinical observations in the literature. The presented analysis is the first step in quantitatively analyzing possible treatment scenarios to find the optimal treatment strategies for PCa using the combination treatment with ADT, NHEJ inhibitors, and IR.

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Impact of IUdR on Rat 9L Glioma Cell Survival for 25–35 keV Photon-Activated Auger Electron Therapy

Alvarez

Hogstrom

Brown

et al. 2014

Radiation Research

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The goal of the current study was to measure the energy dependence of survival of rat 9L glioma cells labeled with iododeoxyuridine (IUdR) that underwent photon-activated Auger electron therapy using 25-35 keV monochromatic X rays, i.e., above and below the K-edge energy of iodine. Rat 9L glioma cells were selected because of their radioresistance, ability to be implanted for future in vivo studies and analogy to radioresistant human gliomas. Survival curves were measured for a 4 MV X-ray beam and synchrotron produced monochromatic 35, 30 and 25 keV X-ray beams. IUdR was incorporated into the DNA at levels of 0, 9 and 18% thymidine replacement for 4 MV and 35 keV and 0 and 18% thymidine replacement for 30 and 25 keV. For 10 combinations of beam energy and thymidine replacement, 62 data sets (3-13 per combination) provided 776 data points (47-148 per combination). Survival versus dose data taken for the same combination, but on different days, were merged by including the zero-dose points in the nonlinear, chi-squared data fitting using the linear-quadratic model and letting the best estimate to the zero-dose plating efficiency for each of the different days be a fitting parameter. When comparing two survival curves, the ratio of doses resulting in 10% survival gave sensitization enhancement ratios (SER10) from which contributions due to linear energy transfer (LET) (SER10,LET), IUdR radiosensitization (SER10,RS), the Auger effect (SER10,AE) and the total of all effects (SER10,T) were determined. At 4 MV and 35, 30 and 25 keV, SER10,LET values were 1.00, 1.08 ± 0.03, 1.22 ± 0.02 and 1.37 ± 0.02, respectively. At 4 MV SER10,RS values for 9 and 18% IUdR were 1.28 ± 0.02 and 1.40 ± 0.02, respectively. Assuming LET effects were independent of percentage IUdR and radiosensitization effects were independent of energy, SER10,AE values for 18% IUdR at 35, 30 and 25 keV were 1.35 ± 0.05, 1.06 ± 0.03 and 0.98 ± 0.03, respectively. The value for 9% IUdR at 35 keV was 1.01 ± 0.04. First, we found the radioresistant rat 9L glioma cell line exhibited an SER10 due to the Auger effect of 1.35 at (35 keV, 18% IUdR) and an SER10 due to the radiosensitizing effect of 1.40 at (4 MV, 18% IUdR), both significantly less than values for previously reported cell lines. These low individual values emphasize the benefit of their combined value (SER10 of approximately 1.9) for achieving clinical benefit. Second, as expected, we observed that energies below the K-edge of iodine (25 and 30 keV), for which there are L, M and higher shell photoelectric events creating Auger electrons, show no promise for Auger electron therapy. Third, to proceed with future in vivo studies, additional data from 35-65 keV are needed to determine the optimal X-ray energy for IUdR Auger electron therapy. Only then can there be an answer to the question, how well the energy dependence of in vitro survival data supports the potential for photon-activated Auger electron therapy with IUdR in cancer radiotherapy.

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Quantitative analysis of the effects of iododeoxyuridine and ionising radiation treatment on the cell cycle dynamics of DNA mismatch repair deficient human colorectal cancer cells

Cited by 3 publications

References 38 publications

One-pot biosynthesis of idoxuridine using nanostabilized lactic acid bacteria

One-pot biosynthesis of idoxuridine using nanostabilized lactic acid bacteria

Computational analysis of androgen receptor dependent radiosensitivity in prostate cancer

Impact of IUdR on Rat 9L Glioma Cell Survival for 25–35 keV Photon-Activated Auger Electron Therapy

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