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Low dose fractionated radiation enhances the radiosensitization effect of paclitaxel in colorectal tumor cells with mutant p53
Author(s) -
Chendil Damodaran,
Oakes Rachael,
Alcock Rachael A.,
Patel Nish,
Mayhew Christopher,
Mohiuddin Mohammed,
Gallicchio Vincent S.,
Ahmed Mansoor M.
Publication year - 2000
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/1097-0142(20001101)89:9<1893::aid-cncr4>3.0.co;2-b
Subject(s) - paclitaxel , clonogenic assay , ionizing radiation , medicine , cancer research , radiation therapy , radiosensitivity , radioresistance , mutant , western blot , wild type , nuclear medicine , irradiation , cell , chemotherapy , biology , biochemistry , physics , gene , nuclear physics
BACKGROUND The current study was undertaken to investigate the influence of wild‐type or mutant p53 status on the radiosensitizing effect of paclitaxel in colorectal tumor cell lines. METHODS HCT‐116 (contains wild‐type p53) and HT‐29 (contains mutant p53) established from moderately differentiated colorectal carcinomas were used in this study. Colony‐forming assay was performed after exposure to either different radiation doses (0.5–6 gray [Gy]) or paclitaxel (1–10 nM) or in combination. Induction of p53 and p21 waf1/cip1 by these treatments were determined by immunocytochemistry and Western blot analysis. RESULTS Radiation caused an increase in nuclear p53 and p21 waf1/cip1 proteins in HCT‐116 cells, indicating that p53 functionally induced p21 waf1/cip1 . However, induction of nuclear p53 and p21 waf1/cip1 protein was not evident in HT‐29 cells, suggesting that p53 was not functional in these cells. Survival data showed that the HCT‐116 cells (survival fraction of exponentially growing cells that were irradiated at the clinically relevant dose of 2 Gy [SF 2 ] = 0.383; dose required to reduce the fraction of cells to 37% [D 0 ] = 223 centigray [cGy]) were significantly sensitive to ionizing radiation ( P < 0.008) when compared with the HT‐29 cells (SF 2 = 0.614; D 0 = 351 cGy). Paclitaxel caused a higher degree of clonogenic inhibition in HCT‐116 (D 0 = 0.7 nM) than HT‐29 (D 0 = 1.11 nM) cells ( P < 0.06). When paclitaxel and radiation were combined, an enhanced radiosensitizing effect ( P < 0.05) was observed in HCT‐116 cells (SF 2 = 0.138; D 0 = 103 cGy), whereas in HT‐29 cells no significant radiosensitization of paclitaxel was observed (SF 2 = 0.608; D 0 = 306 cGy). However, pretreatment with paclitaxel followed by multifractionated low dose radiation (0.5‐ or 1‐Gy fractions for a total dose of 2 Gy) significantly enhanced the radiosensitizing effect in both HCT‐116 and HT‐29 cells. CONCLUSIONS The results of the current study suggested that multifractionated radiation given at very low doses after exposure of cells to paclitaxel conferred a potent radiation sensitizing effect irrespective of p53 status. Cancer 2000;89:1893–900. © 2000 American Cancer Society.