Human malignant glioma cell lines are sensitive to low radiation doses

Abstract

Malignant gliomas display aggressive local behavior and are not cured by existing therapy. Some cell lines that are considered radioresistant respond to low radiation doses (<1 Gy) with increased cell killing (low-dose hypersensitivity). In our study, 4 of 5 human glioma cell lines exhibited significant X-ray sensitivity at doses below 1 Gy. The surviving fractions (SFs) obtained at 0.7 and/or 0.8 Gy were comparable to those at 1.5 Gy. Low-dose hypersensitivity was evident when irradiation was combined with etoposide treatment. Repeated irradiation with low doses was markedly more effective than irradiation with single, biologically equivalent doses in decreasing SFs, inhibiting xenograft tumor growth in mice. All experiments were conducted with an accelerator used in clinics, establishing that low-dose hypersensitivity was present following megavoltage X-irradiation. Malignant glioma is one of the most radioresistant tumor types and accounts for approximately 60% of all primary brain tumors in adults. The prognosis of malignant glioma patients remains dismal. The standard of care has been essentially unchanged for many decades: surgical resection of as much of the tumor as is safe, followed by radiation therapy and chemotherapy. Even under the best of circumstances, in which essentially all of the tumor seen on magnetic resonance imaging scan can be surgically removed and the patients fully treated with radiation and chemotherapy, mean survival is extended only from 2-3 months to 1 year. [1][2][3] Despite the widespread use of radiation therapy for the treatment of malignant glioma, the uniformly poor response of these tumors remains a critical problem in the management of these patients. 3 Disruption of cell-cycle arrest or apoptotic pathways by INK4a loss or by p53 mutations or inactivation (approx. 40 -60% of malignant gliomas have p53 mutations) associated with CDK4 amplification or Rb loss may be significant factors in determining the response of these tumors to irradiation and treatment outcome. 4 -6 The radiation survival response of mammalian cells is more complicated than once believed. A few studies indicate that some human cell lines are sensitive to killing by low radiation doses (Ͻ1 Gy). This has been termed low-dose hyper-radiosensitivity (HRS). [7][8][9][10][11] This may reflect differential triggering or induction of repair mechanisms. Cells may be sensitive to low doses because repair mechanisms are not induced, whereas higher doses may cause enough damage to induce or trigger repair mechanisms and, therefore, exhibit increased radioresistance. 9 We report here that 4 malignant glioma cell lines displayed a significant increase in X-ray radiosensitivity at doses below 1 Gy compared to the prediction extrapolated from a linear-quadratic (LQ) model that fits to the data at higher doses. In addition, this phenomenon was extended to 4 human melanoma cell lines and MRC5 human fibroblasts. Moreover, ultrafractionated irradiation with low doses was markedly more effective than conventional irradiati...

Low Dose Fractionated Radiation Potentiates the Effects of Taxotere in Nude Mice Xenografts of Squamous Cell Carcinoma of Head and Neck

“…31 However, in another recent report, repeated irradiation with low dose (0.8 Gy 3 times / day for 4 days/week to a total of 2 consecutive weeks) was markedly more effective than irradiation with single conventional dose (2 Gy / day, for 4 days/week to a total of 2 consecutive weeks) in inhibiting the tumor xenograft in mice. 33 The authors implied that the ultra-fractionation as apposed to continuous hyperfractionation accelerated radiotherapy, reduced long-term injuries and prevented tumor repopulation in radioresistant tumors. 33 These reported findings are in concordance with results observed in our study where the LDFRT group showed a significant inhibitory effect and a prolonged tumor regrowth delay when compared with 2 Gy group ( Fig.…”

“…33 The authors implied that the ultra-fractionation as apposed to continuous hyperfractionation accelerated radiotherapy, reduced long-term injuries and prevented tumor repopulation in radioresistant tumors. 33 These reported findings are in concordance with results observed in our study where the LDFRT group showed a significant inhibitory effect and a prolonged tumor regrowth delay when compared with 2 Gy group ( Fig. 2A and B).…”

A concurrent ultra‐fractionated radiation therapy and temozolomide treatment: A promising therapy for newly diagnosed, inoperable glioblastoma

“…[8][9][10][11][12][13][14][15][16][17] Strikingly, this "radiosensitivity" is more apparent in radioresistant cell lines, such as glioma cells. [8][9][10][11][12][13][14][15][16][17] We demonstrated this phenomenon in a number of various human malignant glioma cell lines using a common clinical device for irradiation. 7,17 Daily irradiation with a single biologically equivalent dose resulted in significantly higher cell death (using a clonogenic assay).…”

“…[8][9][10][11][12][13][14][15][16][17] We demonstrated this phenomenon in a number of various human malignant glioma cell lines using a common clinical device for irradiation. 7,17 Daily irradiation with a single biologically equivalent dose resulted in significantly higher cell death (using a clonogenic assay). 7,17 Experiments conducted on glioma xenografts revealed that repeated irradiation with low doses (0.8 Gy, three times a day) is more effective than a single dose (2 or 2.4 Gy, once a day) in inhibiting tumor growth.…”

“…7,17 Daily irradiation with a single biologically equivalent dose resulted in significantly higher cell death (using a clonogenic assay). 7,17 Experiments conducted on glioma xenografts revealed that repeated irradiation with low doses (0.8 Gy, three times a day) is more effective than a single dose (2 or 2.4 Gy, once a day) in inhibiting tumor growth. 7,17 Consequently, in 2003, we began a phase II study testing an ultra-fractionated RT for inoperable de novo GBM.…”