title: Low-dose radiation hypersensitivity in human tumor cell lines: effects of cell-cell contact and nutritional deprivation.
abstract: The hyper-radiosensitivity at low doses recently observed in vitro in a number of cell lines is thought to have important implications for improving tumor radiotherapy. However, cell-cell contact and the cellular environment influence cellular radiosensitivity at higher doses, and they may alter hyper-radiosensitivity in vivo. To confirm this supposition, we investigated the effects of cell density, multiplicity and nutritional deprivation on low-dose hypersensitivity in vitro. Cell survival in the low-dose range (3 cGy to 2 Gy) was studied in cells of two human glioma (BMG-1 and U-87) and two human oral squamous carcinoma (PECA-4451 and PECA-4197) lines using a conventional macrocolony assay. The effects of cell density, multiplicity and nutritional deprivation on hyper-radiosensitivity/induced radioresistance were studied in cells of the BMG-1 cell line, which showed prominent hypersensitivity and induced radioresistance. The induction of growth inhibition, cell cycle delay, micronuclei and apoptosis was also studied at the hyper-radiosensitivity-inducing low doses. Hyper-radiosensitivity/induced radioresistance was evident in the cells of all four cell lines to varying extents, with maximum sensitivity at 10-30 cGy, followed by an increase in survival up to 50 cGy-1 Gy. Both the glioma cell lines had more prominent hyper-radiosensitivity than the two squamous carcinoma cell lines. Low doses inducing maximum hyper-radiosensitivity did not cause significant growth inhibition, micronucleation or apoptosis in BMG-1 cells, but a transient G(1)/S-phase block was evident. Irradiating and incubating BMG-1 cells at high density for 0 or 4 h before plating, as well as irradiating cells as microcolonies, reduced hyper-radiosensitivity significantly, indicating the role of cell-cell contact-mediated processes. Liquid holding of BMG-1 cells in HBSS + 1% serum during and after irradiation for 4 h significantly reduced hyper-radiosensitivity, suggesting that hyper-radiosensitivity may be due partly to active damage fixation processes at low doses. Therefore, our findings suggest that the damage-induced signaling mechanisms influenced by (or mediated through) cell-cell contact or the cellular environment, as well as the lesion fixation processes, play an important role in hyper-radiosensitivity. Further studies are required to determine the exact nature of the damage that triggers these responses as well as for evaluating the potential of low-dose therapy.
authors.affiliation: Institute of Nuclear Medicine & Allied Sciences, Brig. S. K. Mazumdar Road, Delhi, 110054, India. sudhirchandna@yahoo.com
authors.forename: Sudhir
authors.initials: S
authors.lastname: Chandna
authors.forename: B S
authors.initials: BS
authors.lastname: Dwarakanath
authors.forename: Divya
authors.initials: D
authors.lastname: Khaitan
authors.forename: T Lazar
authors.initials: TL
authors.lastname: Mathew
authors.forename: Viney
authors.initials: V
authors.lastname: Jain
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D001932:Brain Neoplasms; D002450:Cell Communication / Q000528:radiation effects*; D002452:Cell Count; D002453:Cell Cycle / Q000528:radiation effects*; D002455:Cell Division / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects*; D003470:Culture Media; D004307:Dose-Response Relationship, Radiation; D005910:Glioma; D006801:Humans; D048629:Micronuclei, Chromosome-Defective / Q000528:radiation effects; D015162:Micronucleus Tests; D011836:Radiation Tolerance / Q000528:radiation effects; D014407:Tumor Cells, Cultured
chemical_list: D003470:Culture Media