Thep53 gene is a potent determinant of chemosensitivity and radiosensitivity in gastric and colorectal cancers

Hamada, Masanori; Fujiwara, Toshiyoshi; Hizuta, Akio; Gochi, Akira; Naomoto, Yoshio; Takakura, Norihisa; Takahashi, Kenji; Roth, Jack A.; Tanaka, Noriaki; Orita, Kunzo

doi:10.1007/bf01220804

Cited by 105 publications

(47 citation statements)

References 15 publications

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“…These data are consistent with those of others which demonstrate the existence of a p53-independent response to DNA damage (Liebermann et al, 1995) and that wild type p53 mediates the apoptotic response to anticancer drugs . Indeed, it has been previously shown in a variety of cell lines, that mutant p53 confers resistance to DNA damaging agents (Lee and Bernstein, 1993;Eliopoulos et al, 1995;Hamada et al, 1996). p53-null tumors rarely occur in vivo.…”

Section: Discussionmentioning

confidence: 99%

Mutant p53 protein expression interferes with p53-independent apoptotic pathways

et al. 1998

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Loss of normal p53 function was found frequently to interfere with response of cancer cells to conventional anticancer therapies. Since more than half of all human cancers possess p53 mutations, we decided to explore the involvement of mutant p53 in drug induced apoptosis. To further evaluate the relationship between the p53-dependent and p53-independent apoptotic pathways, and to elucidate the function of mutant p53 in modulating these processes, we investigated the role of a p53 temperature-sensitive (ts) mutant in a number of apoptotic pathways induced by chemotherapeutic drugs that are currently used in cancer therapy. To that end, we studied the M1/2, myeloid p53 non-producer cells, and M1/2-derived temperature-sensitive mutant p53 expressing clones. Apoptosis caused by DNA damage induced with g-irradiation, doxorubicin or cisplatin, was enhanced in cells expressing wild type p53 as compared to that seen in parental p53 non-producer cells; mutant p53 expressing clones were found to be more resistant to apoptosis induced by these factors. Actinomycin D, a potent inhibitor of transcription, as well as a DNA damaging agent, abrogated the restraint apoptosis mediated by mutant p53. These observations suggest that while loss of wild type p53 function clearly reduces the rate of apoptosis, p53 mutations may result in a gain of function which signi®cantly interferes with chemotherapy induced apoptosis. Therefore, to achieve a successful cancer therapy, it is critical to consider the speci®c relationship between a given mutation in p53 and the chemotherapy selected.

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Section: Discussionmentioning

confidence: 99%

Mutant p53 protein expression interferes with p53-independent apoptotic pathways

et al. 1998

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“…The presence of p53 mutations was found to predict worse prognosis and reduced response to therapy in many (Lowe, 1995;El Rouby et al, 1993;Wattel et al, 1994;Rusch et al, 1995;Righetti et al, 1996;Traubert et al, 1996;Hamada et al, 1996;Goh et al, 1995), though not all (Makris et al, 1995;Mathieu et al, 1995;Cote et al, 1997), tumors. Loss of wt p53 activity could potentially account fully for the increased radio-and chemoresistance of tumors bearing p53 mutations.…”

Section: Introductionmentioning

confidence: 99%

Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy

1999

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Many tumors overexpress mutant forms of p53. A growing number of studies suggest that the nature of a p53 mutation in a cell can impact upon cellular properties, clinical responses to therapy and prognosis of a tumor. To explore the cellular basis of these observations, experiments were designed to compare the properties of cells with and without p53 mutations within the same cell population. To that end, various tumorderived human p53 mutants were introduced into p53-null H1299 lung adenocarcinoma cells. Clonogenic survival assays revealed that cells overexpressing the p53His175 mutant, but not the p53His273 mutant, recover preferentially from etoposide treatment. Moreover, p53His175 as well as p53His179 reduced substantially the rate of etoposide-induced apoptosis, whereas p53His273 and p53Trp248 had a much milder protective e ect. In contrast, p53His175 and p53His273 exerted very similar e ects on the cellular response to cisplatin; both conferred increased resistance to low concentrations of the drug (2.5 mg/ml), but did not protect at all against high concentrations (10 mg/ml). Hence particular p53 mutants may confer upon tumor cells a selective survival advantage during chemotherapy. These ®ndings de®ne a new type of mutant p53 selective gain of function, which may compromise the e cacy of cancer chemotherapy.

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“…The absence of wild-type p53 function results in the cellular resistance to anticancer agents such as 5-FU and cisplatin in several cell lines, including gastric cancer (Nabeya et al, 1995;Harris, 1996). In addition, several investigators have demonstrated the correlation between the immunohistochemical overexpression of p53 in primary gastric cancer and the resistance to cisplatin-contained regimens (Hamada et al, 1996;Cascinu et al, 1998;Nakata et al, 1998).…”

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confidence: 99%

Immunostaining of thymidylate synthase and p53 for predicting chemoresistance to S-1/cisplatin in gastric cancer

et al. 2007

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High expression of thymidylate synthase (TS) and inactivation of p53 are allegedly associated with chemoresistance. The authors evaluated TS and p53 expression in gastric cancer treated with neoadjuvant S-1/cisplatin chemotherapy. Paraffin sections of pretreatment biopsy and surgical specimens from 41 gastric cancers were immunostained for TS and p53 protein after appropriate antigen retrieval. Fifty-one cases without neoadjuvant chemotherapy were also studied. In the pretreatment biopsies, high expression of TS was seen in 8% of the histologic responders, in 28% of the nonresponders and in 31% of the controls. High expression of p53 was observed in 56% of the nonresponders, but in 8% of the responders and in 29% of the controls (Po0.01 and Po0.05, respectively). The TS-and/or p53-high phenotype was seen in 76% of the nonresponders and in 54% of the controls, but in 8% of the responders (Po0.0001 and Po0.005, respectively). The data of the surgical specimens were consistent with those of the pretreatment biopsies. These results suggest that immunostaining for TS and p53 protein is useful for pretreatment selection of gastric cancer patients unresponsive to S-1/cisplatin chemotherapy.

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Thep53 gene is a potent determinant of chemosensitivity and radiosensitivity in gastric and colorectal cancers

Cited by 105 publications

References 15 publications

Mutant p53 protein expression interferes with p53-independent apoptotic pathways

Mutant p53 protein expression interferes with p53-independent apoptotic pathways

Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy

Immunostaining of thymidylate synthase and p53 for predicting chemoresistance to S-1/cisplatin in gastric cancer

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