Combination of p53 codon 72 polymorphism and inactive p53 mutation predicts chemosensitivity to 5‐fluorouracil in colorectal cancer

Abstract

There are increasing reports showing the clinical significance of the p53 polymorphism status in terms of the response to chemotherapy. We investigated whether p53 polymorphism and mutation were associated with in vitro sensitivity to 5-fluorouracil (5-FU) in patients with colorectal cancer. Chemosensitivity to 5-FU was evaluated by the collagen gel droplet embedded culture drug sensitivity test. 5-FU sensitivity of tumor cells without inactive p53 mutation in the arginine/arginine (Arg/Arg) variant was significantly higher than that of tumor cells with or without inactive p53 mutation in other variants (p 5 0.022), whereas the 5-FU sensitivity of tumor cells with inactive p53 mutation in the Arg/Arg variant was significantly lower than that of tumor cells with or without inactive p53 mutation in other variants (p 5 0.002). In the Arg/Arg variant, apoptotic cells induced by 5-FU treatment in patients without inactive p53 mutation were more markedly increased than those in patients with inactive p53 mutation (p 5 0.037). Bax and Bcl-2 protein expressions in tumor tissue treated with 5-FU were associated with both 5-FU sensitivity and the apoptotic cell count. Our data show that the Arg/Arg genotype without inactive p53 mutation could be predictive of a more favorable response and the Arg/Arg genotype with inactive p53 mutation a less favorable response to chemotherapy using 5-FU in CRC. The combination of the p53 codon 72 polymorphism and p53 mutation status is a potential predictive marker of sensitivity to 5-FU in CRC.The p53 tumor suppressor gene encodes a nuclear protein that induces growth arrest or apoptosis in response to cellular stress. 1 Apoptosis is a fundamental mechanism by which DNA-damaging anticancer agents cause cytotoxicity. 2 p53 has a major function in transducing stress to the apoptotic machinery of cells, consistent with the importance of the p53 status as a determinant of the cellular response to DNA-damaging drugs. 3,4 The presence of an intact p53 function confers tumor sensitivity to DNA-damaging agents such as cisplatin. 5 However, p53 is mutated in at least 50% of human cancers. 6 The mutation site is widely distributed in DNA-binding domain including the amino acid part that is called hot spot as codons 175, 245, 248, 249, 273 and 282. In a recent analyses with a large number of patients, type of mutation (inactive TP53 mutations) and adjuvant treatment were identified as important factors in determining the prognostic significance of p53 mutation in colorectal cancer (CRC). 7,8 Another recent study has quantitated the functional activity of different p53 mutation with respect to their ability to transactivate target genes. There were 3 subtypes: mutants with no activity, mutants with significantly reduced but some residual activity and mutants with activity comparable with that of wild-type p53. 9 The most common p53 mutation in human tumors show a clear loss of transactivation activity. 10 We can designate p53 hot spot mutation as inactive p53 mutation. Inactive p53 mutation is impo...

RETRACTED ARTICLE: P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance

“…Therefore, p38MAPK could be included in a future list of putative prognosis markers for 5-FU-based therapy, as it is the case of apoptotic proteins (Hector and Prehn, 2009). In view of the connection between p53, a known marker of 5-FU-based therapy even at the clinical level (Nabeya et al, 1995;Zheng et al, 1999;Tominaga et al, 2010), and p38MAPK signaling pathway, it seems logical to consider further studies to fully establish the role of p38MAPK as a biomarker for 5-FU-based therapy. Thus, and considering previous evidences with ara-C (Sanchez-Arevalo, et al, 2005), we demonstrate a major role for the p38MAPK signaling pathway in antimetabolites-based therapy.…”

“…One of the major problems associated with 5-FU therapy is the development of resistance to the drug. Resistance to 5-FU may occur by a number of mechanisms, including alterations in the enzymes implicated in the metabolism or in the mechanism of action of the drug, especially in the target enzyme (for review, see Peters et al, 2002), also, alterations in molecules such as p53 (Lowe et al, 1993;Bunz et al, 1999;Longley et al, 2002;Tominaga et al, 2010) and in proteins critical in the response to DNA damage, such as ataxia telangiectasia mutated (ATM) or ataxia telangiectasia and Rad3 related (ATR) (for review, see Wyatt and Wilson III, 2009). For example, ATR has been shown to be an essential mediator in the antitumoral properties of 5-FU (Wilsker and Bunz 2007) through the control exerted on the mismatch repair system (Liu et al, 2008) or on CHK1, a regulatory component of the DNA damage checkpoint (Jardim et al, 2009).…”

Decrease of survivin, p53 and Bcl-2 expression in chemorefractory colorectal liver metastases may be predictive of radiosensivity after radioembolization with yttrium-90 resin microspheres

“…In fact, mild manifestations of non-alcoholic fatty liver disease (NAFLD) after 5FU [26], more serious non-alcoholic steatohepatitis after irinotecan and sinusoidal obstruction syndrome (SOS) after oxaliplatin-based treatment [27] have been recorded. Using the same biomarkers as in our study, Panasiuk and colleagues [28] showed that the intensification of inflammation in NAFLD may also impact on biomarker expression in human hepatocytes with the induction of pro-apoptotic protein p53 and the inhibition of anti-apoptotic Bcl-2.…”

Pharmacological inhibition of Mdm2 triggers growth arrest and promotes DNA breakage in mouse colon tumors and human colon cancer cells

“…The role of p53 in preventing colon cancer progression and improving patient response to therapy is well-documented [25–29]. The pharmacological enhancement of p53 activity in colon cancers maintaining a functional p53 gene may therefore be an effective and relatively safe therapeutic approach.…”