ERCC1 expression in patients with colorectal cancer: a pilot study

Abstract

Aim: Excision repair cross complementation group 1 (ERCC1) has a key role in enhanced DNA damage repair caused by oxaliplatin-based therapy and may lead to resistance of these platinum drugs in colorectal cancer (CRC) patients. Hence, the present preliminary study aimed to explore the role of ERCC1 C/T polymorphism at codon 118 as well as its immunoreactivity in patients with primary CRC. Methods: ERCC1 polymorphism was studied using PCR-RFLP and ERCC1 protein expression was examined by immunohistochemistry in 50 CRC patients. Results: ERCC1 codon 118 C/T polymorphism analysis reported the predominance of C/T (52%) genotype as compared to C/C (38%) and T/T (10%) genotypes. Furthermore, 72% of patients showed positive ERCC1 protein expression. Significant correlation was not observed between clinicopathological parameters and ERCC1 polymorphism, while ERCC1 protein expression significantly correlated only with tumor site (colon vs. rectum) (P = 0.046). Further, the present study failed to demonstrate the role of ERCC1 C118T polymorphism or protein expression as useful prognostic markers in CRC patients. Conclusion: ERCC1-positive protein expression may be a useful marker for rectal cancer patients. However, further evaluation in a larger set of CRC patients is required to better understand the role of ERCC1. Key words:Excision repair cross complementation group 1, oxaliplatin, colorectal cancer, polymorphism, protein expression, PCR-RFLP, immunohistochemistry ABSTRACTArticle history:

Targeting DNA Repair in Tumor Cells via Inhibition of ERCC1–XPF

“…The previous method was employed to synthesize compound 5 with the following stoichiometric amounts; 1-(3,4-dichlorophenyl)piperazine (0.23 g, 1.0 mmol), acetaminophen (0.15 g, 1.0 mmol), 37% formaldehyde (0.10 mL, 5 mmol), and 6,9-dichloroacridine (0.28 g, 1.0 mmol) to afford 5 as orange reddish semisolid (0.16 g) in 71% yield; R f 0.56 (0.5:9.5, MeOH/DCM); IR (cast film) ν max = 3271, 2918, 1736, 1563, 1227, 1180, 1080, 1031, 803, 721 cm −1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 8.09 (s, 1H), 8.00 (s, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 9.0 Hz, 1H), 7.09 (s, 1H), 6.95 (d, J = 2.8 Hz, 1H), 6.87 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 6.73 (dd, J = 8.9, 2.8 Hz, 1H), 6.54 (d, J = 2.6 Hz, 1H), 3.74 (s, 3H), 3.63 (s, 2H), 3.27−3.15 (m, 4H), 2.72−2.62 (m, 4H), OH and NH protons were not observed; 13 2-((4-(Bis(4-fluorophenyl)methyl)piperazin-1-yl)methyl)-4-((6chloro-2-methoxyacridin-9-yl)amino)phenol (6). The previous method was employed to synthesize compound 6 with the following stoichiometric amounts: 1-bis(4-fluorophenyl)methylpiperazine (0.29 g, 1.0 mmol), acetaminophen (0.15 g, 1.0 mmol), 37% formaldehyde (0.10 mL, 5 mmol), and 6,9-dichloroacridine (0.28 g, 1.0 mmol) to afford 6 as orange reddish semisolid (0.19 g) in 65% yield; R f 0.56 (0.5:9.5, MeOH/DCM); IR (cast film) ν max = 3275, 2919, 1737, 1566, 1255, 1217, 1181, 1032, 828, 722 cm −1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 8.07 (s, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.34 (m, 6H), 7.18 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 1.8 Hz, 1H), 6.97 (m, 5H), 6.83 (dd, J = 8.5, 2.6 Hz, 1H), 6 4-((6-Chloro-2-methoxyacridin-9-yl)amino)-2-((4-(4hydroxyphenyl)piperazin-1-yl)methyl)phenol (7). The previous method was employed to synthesize compound 7 with the following stoichiometric amounts; 1-(4-hydroxyphenyl)piperazine (0.30 g, 1.0 mmol), acetaminophen (0.15 g, 1.0 mmol), 37% formaldehyde (0.10 mL, 5 mmol), and 6,9-dichloroacridine (0.28 g, 1.0 mmol) to afford 7 as orange reddish semisolid (0.17 g) in 59% yield; R f 0.58 (1.…”

“…It plays a pivotal role in nucleotide excision repair (NER) of bulky adducts and helix-distorting DNA lesions such as UV-induced pyrimidine-(6,4)-pyrimidone photoproducts (6-4PPs) and CPDs. − ERCC1–XPF is also involved in DNA interstrand cross-link (ICL) repair in cells treated with platinum-based and other chemotherapeutic agents such as cyclophosphamide and mitomycin C (MMC) . In a recent study, 72% of colorectal cancer patients showed positive ERCC1 protein expression, which may be a useful marker for colorectal cancer patients . There is also evidence that ERCC1–XPF participates in DNA double-strand break (DSB) repair. , It thus contributes significantly to the response of cancer cells to a range of DNA-damaging chemotherapeutic agents and radiotherapy.…”

“…6 In a recent study, 72% of colorectal cancer patients showed positive ERCC1 protein expression, which may be a useful marker for colorectal cancer patients. 7 There is also evidence that ERCC1−XPF participates in DNA double-strand break (DSB) repair. 8,9 It thus contributes significantly to the response of cancer cells to a range of DNA-damaging chemotherapeutic agents and radiotherapy.…”

Targeting the DNA Damage Response for Cancer Therapy

“…They crosslink DNA molecules, causing extensive DNA damage and triggering apoptosis in cancer cells. However, in many cancer cells, the NER pathway is overactive due to the overexpression of ERCC1, which can diminish the therapeutic effectiveness of cisplatin and even lead to drug resistance [165][166][167][168]. Therefore, the design of selective NER/ERCC1 inhibitors holds promise in the enhancement of the efficacy of platinum-based treatments.…”

Excision repair cross-complementing group-1 (ERCC1) induction kinetics and polymorphism are markers of inferior outcome in patients with colorectal cancer treated with oxaliplatin

“…There is evidence that the relative level of ERCC1 mRNA is a good marker for NER activity in human cancer cells, but it is unclear whether expression of this gene is important for other pathways of DNA repair [19, 20]. It has been previously shown that a high basal levels of ERCC1 is associated with poorer survival in patients with mCRC treated with oxaliplatin [21], although, surprisingly, no difference in tumor response was found [22, 23]. Although platinum drugs predominantly result in bulky DNA-distorting adducts and elicit NER, they can also induce inter-strand crosslinks that are repaired by the Fanconi pathways during S phase.…”