No 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...

Although the induction of pigmentation following exposure of melanocytes to ultraviolet light in vivo and in vitro is well documented, the intracellular mechanisms involved in this response are not yet fully understood. Exposure to UV-B radiation leads to the production of DNA damage, mainly cyclobutane pyrimidine dimers, and it was recently suggested that the thymidine dinucleotide pTpT, mimicking small DNA fragments released in the course of excision repair mechanisms, could trigger melanin synthesis. We now report that the thymidine dinucleotide pTpT induces melanogenesis both in human normal adult melanocytes and in human melanoma cells. Thus, the SOS-like response suggested by Gilchrest's work to be evolutionary conserved, based primarily on work in murine cells and guinea pigs, is also apparently present in the human. Thymidine dinucleotide is nontoxic to melanoma cells and does not induce apoptosis in these cells, but induces S phase cell cycle arrest and a proliferation slow down. Because thymidine excess in culture medium leads to the synchronization of cells in S phase, we investigated whether this phenomenon was involved in the increase in melanin synthesis. We show that melanin synthesis is specifically triggered by the dimeric form of the thymidine and not by the monomeric form pT. Thus, our data strongly support that thymidine dinucleotides pTpT mimic at least part of the effects of ultraviolet irradiation, and may hence represent an invaluable model in the study of the molecular events involved in melanogenesis induction triggered through DNA damage.