P53 overexpression predicts poor chemosensitivity to high‐dose 5‐fluorouracil plus leucovorin chemotherapy for stage IV colorectal cancers after palliative bowel resection

Abstract

Our study aims to further clarify the prognostic significance of p53 overexpression in stage IV colorectal cancer. Between January 1994 and June 1997, we recruited 144 patients with stage IV colorectal cancers for our study, based on appropriate eligibility criteria. The patients were nonrandomly allocated to 2 treatment groups of either with or without high-dose 5-fluorouracil plus leucovorin chemotherapy (HDFL: 5-Fu: 2,600 mg/m 2 leucovorin 300 mg/m maximum 500 mg). Each treatment group was further divided into 2 subgroups according to the status of p53 overexpression. Therefore, 4 subgroups were allocated in our study and were designated as p53 (overexpression) HDFL (؉), n ‫؍‬ 65; p53 (normal) HDFL (؉), n ‫؍‬ 37; p53 (overexpression) HDFL (؊), n ‫؍‬ 27; and p53 (normal) HDFL (؊), n ‫؍‬ 15, respectively. All patients were prospectively followed until April 2001. There was no significant difference of the background clinicopathologic data of these 4 allocated subgroups of patients (p > 0.05). Multivariate analysis of various clinicopathologic factors of the whole group of patients indicated that age >60 years, poor differentiation, mucin production, CEA >100 ng/ml, p53 overexpression and without chemotherapy were the significant independent poor prognostic factors (p < There is generally acceptance of the important role of p53 as "guardian of genome," i.e., as regulator of cell proliferation, differentiation, DNA repair (response to DNA damage) and apoptosis. 1-8 Moreover, according to the "molecular paradigm" of colorectal carcinogenesis, as pointed out by Fearon and Vogelstein, p53 mutation is involved in the later stage of adenoma-carcinoma sequence. 9 Therefore, we have good reasons to speculate that colorectal cancers with p53 mutations might be more aggressive in biologic behavior. In fact, numerous investigators have attempted to correlate this important molecular marker with the clinical outcome of colorectal cancers. 10 -12 However, results reported to date have been controversial. [13][14][15][16][17][18][19] The inconsistency of the clinical relevance of p53 mutations in different studies resulted from different methodology and interpretation criteria used for the assessment of p53 status, 20 -26 different clinical treatment modalities used for patients 27,28 and the variations in clinicopathologic characteristics of the included patients, in particular in regard to pTNM, staging grouping and residual tumor (R) classification. 29 -32 Furthermore, theoretically, tumor prognosis is determined by intrinsic aggressiveness and/or potential sensitivity to chemotherapy. However, although some authors strongly advocate that colorectal cancers with p53 mutations are associated with poor clinical prognosis, we are not fully convinced whether it is due to their chemotherapeutic insensitivity and/or more biologic invasiveness. [33][34][35][36][37][38][39][40][41][42][43] Therefore, the clinical implications of p53 alterations remain obscure and deserve further investigation. Further clarification of the progno...

Characterization of p53 Wild-Type and Null Isogenic Colorectal Cancer Cell Lines Resistant to 5-Fluorouracil, Oxaliplatin, and Irinotecan

“…Several clinical studies have also reported that p53 overexpression, which is often used as a surrogate marker for p53 mutation, correlates with resistance to 5-FU (17)(18)(19), although a number of studies have reported no correlation between p53 expression levels and 5-FU response (20,21). At present, despite compelling in vitro data, the clinical usefulness of p53 as a predictive marker for 5-FU-based chemotherapy remains a matter for debate.…”

“…Total RNA was isolated using the RNA STAT-60 reagent (Biogenesis, Poole, United Kingdom) according to the manufacturer's instructions. Reverse transcription was carried out with 1 g of RNA in a total 10-l reaction volume containing 4 l of RT buffer (ϫ5), 1 l of deoxynucleoside triphosphates (10 mM), 2 l of DTT (0.1 M), 1 l of oligo (dT) [12][13][14][15][16][17][18] primer (500 g/ml), 1 l of RNase OUT (40 units/l), and 1 l of Moloney murine leukemia virus reverse transcriptase (200 units/l; all from Invitrogen Life Technologies). The mixture was incubated for 50 min at 37°C, heated for 10 min at 70°C, and then immediately chilled on ice.…”

Genetic factors influencing Pyrimidine-antagonist chemotherapy

“…[160][161][162][163][164][165][166][167][168] Here, we will only briefly report on the putative role of p53 with respect to 5-FU efficacy, as this relationship has been most extensively studied. Mutations in the p53 gene and p53 overexpression have been associated with 5-FU chemoresistance both in vitro [169][170][171] and in vivo in colorectal, 124,[172][173][174][175] head and neck, 176,177 and breast cancer. 178 However, results in some other studies are less unequivocal.…”

Genetic determinants for activated fluoropyrimidine chemotherapy

“…Patients with mutated p53 or expressing high levels of p53 were less likely to respond to FP chemotherapy than those with wt p53 or those that expressed low levels of p53 . A more recent retrospective study also found patients with stage IV colon cancer that had low levels of p53 responded more favorably to 5FU chemotherapy than patients with high levels of p53 [Liang et al, 2002]. This same study found that high levels of p53 decreased chemosensitivity of tumors, but were not associated with a greater level of inherent biologic aggressiveness in tumors.…”