title: The role of ABC transporters in progression and clinical outcome of colorectal cancer.
abstract: Worldwide, colorectal cancer (CRC) is the third most common cancer, with the highest mortality rates occurring in Central Europe. The use of chemotherapy to treat CRC is limited by the inter-individual variability in drug response and the development of cancer cell resistance. ATP-binding cassette (ABC) transporters play a crucial role in the development of resistance by the efflux of anticancer agents outside of cancer cells. The aim of this study was to explore transcript levels of all human ABCs in tumours and non-neoplastic control tissues from CRC patients collected before the first line of treatment by 5-fluorouracil (5-FU)-containing regimen. The prognostic potential of ABCs was evaluated by the correlation of transcript levels with clinical factors. Relations between transcript levels of ABCs in tumours and chemotherapy efficacy were also addressed. The transcript profile of all known human ABCs was assessed using real-time polymerase chain reaction with a relative standard curve. The majority of the studied ABCs were down-regulated or unchanged between tumours and control tissues. ABCA12, ABCA13, ABCB6, ABCC1, ABCC2 and ABCE1 were up-regulated in tumours versus control tissues. Transcript levels of ABCA12, ABCC7 and ABCC8 increased in direction from colon to rectum. Additionally, transcript levels of ABCB9, ABCB11, ABCG5 and ABCG8 followed the reverse significant trend, i.e. a decrease in direction from colon to rectum. The transcript level of ABCC10 in tumours correlated with the grade (P = 0.01). Transcript levels of ABCC6, ABCC11, ABCF1 and ABCF2 were significantly lower in non-responders to palliative chemotherapy in comparison with responders. The disease-free interval of patients treated by adjuvant chemotherapy was significantly shorter in patients with low transcript levels of ABCA7, ABCA13, ABCB4, ABCC11 and ABCD4. In conclusion, ABCC11 may be a promising candidate marker for a validation study on 5-FU therapy outcome.
authors.affiliation: Toxicogenomics Unit, National Institute of Public Health, Srobarova 48, Prague 10, 100 42 Czech Republic.
authors.forename: I
authors.initials: I
authors.lastname: Hlavata
authors.forename: B
authors.initials: B
authors.lastname: Mohelnikova-Duchonova
authors.forename: R
authors.initials: R
authors.lastname: Vaclavikova
authors.forename: V
authors.initials: V
authors.lastname: Liska
authors.forename: P
authors.initials: P
authors.lastname: Pitule
authors.forename: P
authors.initials: P
authors.lastname: Novak
authors.forename: J
authors.initials: J
authors.lastname: Bruha
authors.forename: O
authors.initials: O
authors.lastname: Vycital
authors.forename: L
authors.initials: L
authors.lastname: Holubec
authors.forename: V
authors.initials: V
authors.lastname: Treska
authors.forename: P
authors.initials: P
authors.lastname: Vodicka
authors.forename: P
authors.initials: P
authors.lastname: Soucek
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D016022:Case-Control Studies; D017024:Chemotherapy, Adjuvant; D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D009362:Neoplasm Metastasis; D010865:Pilot Projects; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012007:Rectum / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
chemical_list: C000715087:ABCC2 protein, human; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D000089762:Multidrug Resistance-Associated Protein 2; D012333:RNA, Messenger