Sublethal damage repair capacity in carcinoma cell lines with p53 mutations

Pekkola‐Heino, Kirsi; Servomaa, Kristina; Kiuru, Anne; Grénman, Reidar

doi:10.1002/(sici)1097-0347(199807)20:4<298::aid-hed3>3.0.co;2-u

Cited by 15 publications

(12 citation statements)

References 27 publications

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“…Generally, alterations of the p53 gene have been shown to contribute to tumorigenesis and drug resistance by modulating apoptotic response (37) and enhancing sublethal damage repair capacity (38). In a recent study it was shown, that HNSCC cell lines differ in their sensitivity against cisplatin depending on their p53 status (17).…”

Section: Resultsmentioning

confidence: 99%

Reduced Cisplatin Sensitivity of Head and Neck Squamous Cell Carcinoma Cell Lines Correlates with Mutations Affecting the COOH-Terminal Nuclear Localization Signal of p53

Mandic

Schamberger²,

Müller

et al. 2005

Clinical Cancer Research

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Purpose: Head and neck squamous cell carcinomas (HNSCC) are the most frequent malignancies of the upper aerodigestive tract. Cisplatin resistance is a major problem in the treatment of a large number of HNSCC cancer patients. In this study, nine randomly selected HNSCC cell lines were investigated regarding expression, presence of mutations, nucleocytoplasmic distribution of p53, and sensitivity to cisplatin. Experimental Design: Protein expression was evaluated by Western blot analysis. The whole open reading frame of p53 was determined by reverse transcription-PCR sequencing. Nucleocytoplasmic distribution was evaluated by confocal laser scanning microscopy. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assay was used to test for cisplatin sensitivity. Results: p53 mutations were found in all nine investigated HNSCC cell lines. Nuclear p53 signal was detected in six cell lines, whereas three cell lines exhibited total loss of nuclear p53 signal. Nuclear signal depended on the presence or absence of the COOH-terminal nuclear localization signal in p53. Cisplatin sensitivity was highly reduced in the group with loss of nuclear p53 signal compared with those with detectable nuclear signal. Transfection of wild-type and mutant p53 into a rat embryonic cell system showed highly reduced activity of the nuclear localization signal mutant p53 protein.Conclusion: Taken together, these data suggest that ''loss of nuclear p53 signal''correlates with cisplatin resistance in HNSCC. If these results can be validated on a larger number of tumor samples, including fresh tumor tissues, it potentially could help in sparing a subgroup of HNSCC patients the side effects associated with unnecessary chemotherapy by identifying cisplatin nonresponders before chemotherapy induction. Head and neck squamous cell carcinomas (HNSCC) accountfor the vast majority (>90%) of malignancies found in the upper aerodigestive tract. They are characterized by their early predominantly lymphatic metastatic spread (1, 2). For over 30 years now, there was no significant improvement of the patient survival time regardless of new developments in surgical techniques as well as in the chemo(radio)therapy treatment scheme of this tumor entity. Despite successful surgical removal of the primary tumor, which can be achieved in most cases, a high number of patients already developed regional lymph node or distant metastases at the time of diagnosis. The treatment scheme of this head and neck cancer, therefore, frequently includes additional surgery to remove tumorrelated lymph nodes (neck dissection) and postoperative chemo(radio)therapy or in the case surgery is not possible because of advanced tumor stage for example, primary chemo(radio)therapy. Postoperative survival of patients with regional lymph node or distant metastases then largely depends on the success of chemo(radio)therapy. Frequently, however, patients relapse after chemo(radio)therapy. Then, after having exhausted the full dose of local radiotherapy, chemo...

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Section: Resultsmentioning

confidence: 99%

Reduced Cisplatin Sensitivity of Head and Neck Squamous Cell Carcinoma Cell Lines Correlates with Mutations Affecting the COOH-Terminal Nuclear Localization Signal of p53

Mandic

Schamberger²,

Müller

et al. 2005

Clinical Cancer Research

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“…PLDR is defined as repair that occurs when plateau phase cells were allowed to remain in the density-inhibited state for 6 to 12 hours after irradiation (Hall et al 2010). There are many reports that have studied different aspects of SLDR, such as cell cycle distribution (Zaider et al 1996), later tissue response (Brenner et al 1998), p53 (a tumor suppressor) involved effects (Pekkola-Heino et al 1998); halftime for SLDR (Guerrero et al 2006); intrinsic radiosensitivity and SLDR (Guerrero et al 2006), implication (Liu et al 2011) and inhibition of SLDR (Ben-Hur et al 2012), etc. One earlier study reported that SLDR depended on HRR in chicken DT40 cells (Utsumi et al 2001) and a recent study reported that SLDR mainly depended on Ku-dependent NHEJ in CHO cells (Somaiah et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Ku-dependent non-homologous end-joining as the major pathway contributes to sublethal damage repair in mammalian cells

Liu

Lee

Liu

et al. 2015

International Journal of Radiation Biology

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Purpose Sublethal damage repair (SLDR) is a type of repair that occurs in split dose irradiated cells, which was discovered more than 50 years ago. However, due to conflicting reported data, it remains unclear which DNA double strand break (DSB) repair pathway, non-homologous end-joining (NHEJ) repair, homologous recombination repair (HRR) or both, contributes to SLDR, particularly in human cells. We were interested in clarifying this question. Methods and materials Mammalian cell lines, including human, mouse and Chinese hamster ovary (CHO) cell lines, wild type, deficient in NHEJ or HRR were irradiated with either single dose or two split doses at 2 or 4 hour intervals. The clonogenic assay was used to evaluate these cell radiosensitivities. Results All wild type or HRR deficient cells (including human, mouse and CHO cells) showed a higher survival rate after exposure to split dose versus single dose radiation, however, all classical NHEJ deficient cells (including human, mouse and hamster cells) did not show any apparent sensitivity changes between single dose and split dose irradiation. Conclusion Classical NHEJ mainly contributes to SLDR in mammalian cells (including human cells) cells. These results have the potential to improve radiotherapy.

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“…The radiosensitivity of established cell lines has been studied widely during the last decade. The SF2 values of HNSCC cell lines have varied from 0.10–1.0, and the SF2 has been lower than 0.5 in most cases 17, 26, 27, 28, 29, 30. Table III presents a review of previously published data on radiosensitivity of HNSCC.…”

Section: Discussionmentioning

confidence: 99%

“…In the literature, the intrinsic radiosensitivity of SCC expressed as AUC has been reported to vary from 2.19 Gy–2.35 Gy 12, 32, 33. The AUC values of HNSCC cell lines tested with the 96‐well plate clonogenic assay have ranged from 1.4 Gy–2.6 Gy 17, 22. In our study, the radiosensitivity of HNSCC cell lines expressed as AUC varied from 1.4 Gy–2.1 Gy.…”

Section: Discussionmentioning

confidence: 99%

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Does skin fibroblast radiosensitivity predict squamous cancer cell radiosensitivity of the same individual?

Haikonen

Rantanen

Pekkola

et al. 2002

Intl Journal of Cancer

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Individualization of radiation doses is presumed to result in better radiotherapy outcome. Success rate in measuring radiosensitivity is probably the most limiting factor for present radiosensitivity assays to be introduced into clinical routine. To find a simpler predictive parameter, we compared the radiosensitivity of dermal fibroblasts and head and neck squamous cell carcinoma (SCC) cell lines established from the same individuals. The radiosensitivity was tested using the clonogenic 96-well plate assay. The surviving fraction at 2.0 Gy (SF2) was determined, as well as the mean inactivation dose (AUC) of cancer cells. SF2 of SCC cell lines and skin fibroblasts were 0.25-0.44 and 0.11-0.43, respectively. AUC of SCC cells was 1.4 -2.1 Gy. Dermal fibroblasts were more radiosensitive than SCC cells in 14 of 15 cases. In 1 patient (UT-SCC-8), cancer cells were found to be more radiosensitive than corresponding dermal fibroblasts. There was a clear tendency to a correlation between radiosensitivities of these 2 cell types, but statistical significance was reached only when the data of UT-SCC-8 was excluded. In our material, the intrinsic radiosensitivity of head and neck SCC cells could in most cases be predicted from the intrinsic radiosensitivity of dermal fibroblasts established from the same individual. Surgery and radiation therapy are the cornerstones in the treatment of head and neck squamous cell carcinoma (HNSCC). In most cases these treatment modalities are combined in order to achieve better therapy response. In practice, the given dose of radiation is, however, limited by acute and late side effects. Not only is the prescribed dose a limiting factor in the normal tissue for the treatment but also the fractionation used. In breast cancer patients, identical doses of external radiotherapy have been shown to cause a varying grade of acute and late dermal side effects, and it has been suggested that the radiosensitivity of all cells is genetically determined in each individual. 1,2 In genetic disorders, ataxiatelangiectasia, e.g., the patients are highly radiosensitive both in vitro and in vivo. In theory, in genetically sensitive individuals a lower radiation dose can be given in order to prevent side effects, but this will not necessarily result in a reduced probability of tumour control. 3 It has been estimated that a subgroup of patients with radioresistant fibroblasts might be able to tolerate perhaps up to 40% larger doses without experiencing a significant increase in severe late skin complications. 4 The in vitro radiosensitivity of skin fibroblasts has most often been regarded to correlate with the clinical expression of late skin reactions. [5][6][7][8] On the other hand, a lack of correlation between the intrinsic radiosensitivity of dermal fibroblasts and early skin reactions has been found in the majority of studies. 6,8 -11 Experimental studies have suggested that the in vitro radiosensitivity of tumour cells, estimated by the fraction of surviving cells after a radiation dose of 2.0 Gy (SF...

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Sublethal damage repair capacity in carcinoma cell lines with p53 mutations

Cited by 15 publications

References 27 publications

Reduced Cisplatin Sensitivity of Head and Neck Squamous Cell Carcinoma Cell Lines Correlates with Mutations Affecting the COOH-Terminal Nuclear Localization Signal of p53

Reduced Cisplatin Sensitivity of Head and Neck Squamous Cell Carcinoma Cell Lines Correlates with Mutations Affecting the COOH-Terminal Nuclear Localization Signal of p53

Ku-dependent non-homologous end-joining as the major pathway contributes to sublethal damage repair in mammalian cells

Does skin fibroblast radiosensitivity predict squamous cancer cell radiosensitivity of the same individual?

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