Tumor response to irinotecan is associated with CYP3A5 expression in colorectal cancer

Buck,Emanuel; Sprick,Martin; Gaida,Matthias  M.; Grüllich,Carsten; Weber,Tim  Frederik; Herpel,Esther; Bruckner,Thomas; Koschny,Ronald

doi:10.3892/ol.2019.10043

Tumor response to irinotecan is associated with CYP3A5 expression in colorectal cancer

Authors:
- Emanuel Buck
- Martin Sprick
- Matthias M. Gaida
- Carsten Grüllich
- Tim Frederik Weber
- Esther Herpel
- Thomas Bruckner
- Ronald Koschny
View Affiliations

Affiliations: Department of Gastroenterology, University Hospital Heidelberg, D‑69120 Heidelberg, Germany, HI‑STEM gGmbH/German Cancer Research Center Heidelberg (MRS), D‑69120 Heidelberg, Germany, Department of Pathology, National Center for Tumor Diseases, University Hospital Heidelberg, D‑69120 Heidelberg, Germany, Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, D‑69120 Heidelberg, Germany, Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, D‑69120 Heidelberg, Germany, Institute for Medical Biometry and Informatics, University of Heidelberg, D‑69120 Heidelberg, Germany
Published online on: February 14, 2019 https://doi.org/10.3892/ol.2019.10043
Pages: 3890-3898
Copyright: © Buck et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Recently, a tumor‑autonomous cytochrome P450 (CYP)‑3A5‑mediated resistance to cancer therapy has been demonstrated in pancreatic ductal adenocarcinoma. Expression of CYP3A5, which is involved in the degradation of irinotecan, has also been reported in colorectal cancer (CRC). The aim of the present study was to analyze CYP3A5 expression in the normal colon, colon adenoma, CRC and normal tissues, as well as to examine whether CYP3A5 expression in CRC has an impact on tumor response to irinotecan treatment. Immunohistochemistry was used to assess 85 tissue samples from 65 patients with CRC, along with 15 samples of normal colon and 45 samples of colon adenoma (including tubular, tubulovillous, and sessile serrated adenomas), and a tissue microarray (TMA) comprised of 26 different normal tissue types. Expression of CYP3A5 was evaluated with a semi‑quantitative score. Tumor response to irinotecan therapy was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. In normal tissues, CYP3A5 was expressed in epithelial cells of the colon, gallbladder, kidney, liver, small intestine, stomach, thyroid gland and tonsil, as well as in nerves. Expression in colon mucosa was heterogeneous, with only weak staining in the minority of specimens. CYP3A5 exhibited markedly higher expression in adenomas compared with normal colon tissues. A statistically significant inverse correlation was identified between CYP3A5 expression in CRC tissues and tumor response to irinotecan therapy. Irinotecan treatment itself did not alter CYP3A5 expression in CRC tissues. As CYP3A5 is involved in the degradation of irinotecan, the significantly higher intratumoral expression of CYP3A5 in patients with CRC who do not respond to irinotecan‑based chemotherapy may indicate a causal role of CYP3A5 in tumor resistance.

View Figures

View References

1	MacLeod SL, Nowell S, Massengill J, Jazieh A, McClure G, Plaxco J, Kadlubar FF and Lan NP: Cancer therapy and polymorphisms of cytochromes P450. Clin Chem Lab Med. 38:883–887. 2000. View Article : Google Scholar : PubMed/NCBI
2	Pavek P and Dvorak Z: Xenobiotic-induced transcriptional regulation of xenobiotic metabolizing enzymes of the cytochrome P450 superfamily in human extrahepatic tissues. Curr Drug Metab. 9:129–143. 2008. View Article : Google Scholar : PubMed/NCBI
3	Ding X and Kaminsky LS: Human extrahepatic cytochromes P450: Function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts. Annu Rev Pharmacol Toxicol. 43:149–173. 2003. View Article : Google Scholar : PubMed/NCBI
4	Krishna DR and Klotz U: Extrahepatic metabolism of drugs in humans. Clin Pharmacokinet. 26:144–160. 1994. View Article : Google Scholar : PubMed/NCBI
5	Rochat B: Role of cytochrome P450 activity in the fate of anticancer agents and in drug resistance: Focus on tamoxifen, paclitaxel and imatinib metabolism. Clin Pharmacokinet. 44:349–366. 2005. View Article : Google Scholar : PubMed/NCBI
6	Michael M and Doherty MM: Tumoral drug metabolism: Overview and its implications for cancer therapy. J Clin Oncol. 23:205–229. 2005. View Article : Google Scholar : PubMed/NCBI
7	Yu LJ, Matias J, Scudiero DA, Hite KM, Monks A, Sausville EA and Waxman DJ: P450 enzyme expression patterns in the NCI human tumor cell line panel. Drug Metab Dispos. 29:304–312. 2001.PubMed/NCBI
8	Noll EM, Eisen C, Stenzinger A, Espinet E, Muckenhuber A, Klein C, Vogel V, Klaus B, Nadler W, Rösli C, et al: CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma. Nat Med. 22:278–287. 2016. View Article : Google Scholar : PubMed/NCBI
9	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
10	Ahmed S, Johnson K, Ahmed O and Iqbal N: Advances in the management of colorectal cancer: From biology to treatment. Int J Colorectal Dis. 29:1031–1042. 2014. View Article : Google Scholar : PubMed/NCBI
11	Ciombor KK, Wu C and Goldberg RM: Recent therapeutic advances in the treatment of colorectal cancer. Annu Rev Med. 66:83–95. 2015. View Article : Google Scholar : PubMed/NCBI
12	Gustavsson B, Carlsson G, Machover D, Petrelli N, Roth A, Schmoll HJ, Tveit KM and Gibson F: A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin Colorectal Cancer. 14:1–10. 2015. View Article : Google Scholar : PubMed/NCBI
13	Glimelius B: Benefit-risk assessment of irinotecan in advanced colorectal cancer. Drug Saf. 28:417–433. 2005. View Article : Google Scholar : PubMed/NCBI
14	Schmoll HJ, Van Cutsem E, Stein A, Valentini V, Glimelius B, Haustermans K, Nordlinger B, van de Velde CJ, Balmana J, Regula J, et al: ESMO consensus guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol. 23:2479–2516. 2012. View Article : Google Scholar : PubMed/NCBI
15	Paulik A, Grim J and Filip S: Predictors of irinotecan toxicity and efficacy in treatment of metastatic colorectal cancer. Acta Medica (Hradec Kralove). 55:153–159. 2012. View Article : Google Scholar : PubMed/NCBI
16	Lamba JK, Lin YS, Schuetz EG and Thummel KE: Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev. 54:1271–1294. 2002. View Article : Google Scholar : PubMed/NCBI
17	Lown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage LA, Brown MB, Guo W and Watkins PB: Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest. 99:2545–2553. 1997. View Article : Google Scholar : PubMed/NCBI
18	Bergheim I, Bode C and Parlesak A: Distribution of cytochrome P450 2C, 2E1, 3A4, and 3A5 in human colon mucosa. BMC Clin Pharmacol. 5:42005. View Article : Google Scholar : PubMed/NCBI
19	Bergheim I, Bode C and Parlesak A: Decreased expression of cytochrome P450 protein in non-malignant colonic tissue of patients with colonic adenoma. BMC Gastroenterol. 5:342005. View Article : Google Scholar : PubMed/NCBI
20	Kumarakulasingham M, Rooney PH, Dundas SR, Telfer C, Melvin WT, Curran S and Murray GI: Cytochrome p450 profile of colorectal cancer: Identification of markers of prognosis. Clin Cancer Res. 11:3758–3765. 2005. View Article : Google Scholar : PubMed/NCBI
21	Dong N, Meng F, Wu Y, Wang M, Cui Y and Zhang S: Genetic polymorphisms in cytochrome P450 and clinical outcomes of FOLFIRI chemotherapy in patients with metastatic colorectal cancer. Tumour Biol. 36:7691–7698. 2015. View Article : Google Scholar : PubMed/NCBI
22	Koschny R, Krupp W, Xu LX, Mueller WC, Bauer M, Sinn P, Keller M, Koschny T, Walczak H, Bruckner T, et al: WHO grade related expression of TRAIL-receptors and apoptosis regulators in meningioma. Pathol Res Pract. 211:109–116. 2015. View Article : Google Scholar : PubMed/NCBI
23	Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al: New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 45:228–247. 2009. View Article : Google Scholar : PubMed/NCBI
24	Kolars JC, Lown KS, Schmiedlin-Ren P, Ghosh M, Fang C, Wrighton SA, Merion RM and Watkins PB: CYP3A gene expression in human gut epithelium. Pharmacogenetics. 4:247–259. 1994. View Article : Google Scholar : PubMed/NCBI
25	Anttila S, Hukkanen J, Hakkola J, Stjernvall T, Beaune P, Edwards RJ, Boobis AR, Pelkonen O and Raunio H: Expression and localization of CYP3A4 and CYP3A5 in human lung. Am J Respir Cell Mol Biol. 16:242–249. 1997. View Article : Google Scholar : PubMed/NCBI
26	Raunio H, Hakkola J, Hukkanen J, Lassila A, Päivärinta K, Pelkonen O, Anttila S, Piipari R, Boobis A and Edwards RJ: Expression of xenobiotic-metabolizing CYPs in human pulmonary tissue. Exp Toxicol Pathol. 51:412–417. 1999. View Article : Google Scholar : PubMed/NCBI
27	Thörn M, Finnström N, Lundgren S, Rane A and Lööf L: Cytochromes P450 and MDR1 mRNA expression along the human gastrointestinal tract. Br J Clin Pharmacol. 60:54–60. 2005. View Article : Google Scholar : PubMed/NCBI
28	Westlind-Johnsson A, Malmebo S, Johansson A, Otter C, Andersson TB, Johansson I, Edwards RJ, Boobis AR and Ingelman-Sundberg M: Comparative analysis of CYP3A expression in human liver suggests only a minor role for CYP3A5 in drug metabolism. Drug Metab Dispos. 31:755–761. 2003. View Article : Google Scholar : PubMed/NCBI
29	Koch I, Weil R, Wolbold R, Brockmöller J, Hustert E, Burk O, Nuessler A, Neuhaus P, Eichelbaum M, Zanger U and Wojnowski L: Interindividual variability and tissue-specificity in the expression of cytochrome P450 3A mRNA. Drug Metab Dispos. 30:1108–1114. 2002. View Article : Google Scholar : PubMed/NCBI
30	Bièche I, Narjoz C, Asselah T, Vacher S, Marcellin P, Lidereau R, Beaune P and de Waziers I: Reverse transcriptase-PCR quantification of mRNA levels from cytochrome (CYP)1, CYP2 and CYP3 families in 22 different human tissues. Pharmacogenet Genomics. 17:731–742. 2007. View Article : Google Scholar : PubMed/NCBI
31	Haehner BD, Gorski JC, Vandenbranden M, Wrighton SA, Janardan SK, Watkins PB and Hall SD: Bimodal distribution of renal cytochrome P450 3A activity in humans. Mol Pharmacol. 50:52–59. 1996.PubMed/NCBI
32	Givens RC, Lin YS, Dowling AL, Thummel KE, Lamba JK, Schuetz EG, Stewart PW and Watkins PB: CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults. J Appl Physiol (1985). 95:1297–1300. 2003. View Article : Google Scholar : PubMed/NCBI
33	Baron JM, Höller D, Schiffer R, Frankenberg S, Neis M, Merk HF and Jugert FK: Expression of multiple cytochrome p450 enzymes and multidrug resistance-associated transport proteins in human skin keratinocytes. J Invest Dermatol. 116:541–548. 2001. View Article : Google Scholar : PubMed/NCBI
34	Lechevrel M, Casson AG, Wolf CR, Hardie LJ, Flinterman MB, Montesano R and Wild CP: Characterization of cytochrome P450 expression in human oesophageal mucosa. Carcinogenesis. 20:243–248. 1999. View Article : Google Scholar : PubMed/NCBI
35	Gervot L, Carrière V, Costet P, Cugnenc PH, Berger A, Beaune PH and de Waziers I: CYP3A5 is the major cytochrome P450 3A expressed in human colon and colonic cell lines. Environ Toxicol Pharmacol. 2:381–388. 1996. View Article : Google Scholar : PubMed/NCBI
36	McKinnon RA, Burgess WM, Gonzalez FJ and McManus ME: Metabolic differences in colon mucosal cells. Mutat Res. 290:27–33. 1993. View Article : Google Scholar : PubMed/NCBI
37	Windmill KF, McKinnon RA, Zhu X, Gaedigk A, Grant DM and McManus ME: The role of xenobiotic metabolizing enzymes in arylamine toxicity and carcinogenesis: Functional and localization studies. Mutat Res. 376:153–160. 1997. View Article : Google Scholar : PubMed/NCBI
38	Sheweita SA: Drug-metabolizing enzymes: Mechanisms and functions. Curr Drug Metab. 1:107–132. 2000. View Article : Google Scholar : PubMed/NCBI
39	Erichsen R, Baron JA, Hamilton-Dutoit SJ, Snover DC, Torlakovic EE, Pedersen L, Frøslev T, Vyberg M, Hamilton SR and Sørensen HT: Increased risk of colorectal cancer development among patients with serrated polyps. Gastroenterology. 150:895–902.e5. 2016. View Article : Google Scholar : PubMed/NCBI
40	Nusko G, Mansmann U, Partzsch U, Altendorf-Hofmann A, Groitl H, Wittekind C, Ell C and Hahn EG: Invasive carcinoma in colorectal adenomas: Multivariate analysis of patient and adenoma characteristics. Endoscopy. 29:626–631. 1997. View Article : Google Scholar : PubMed/NCBI