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Implications of Genetic Testing in the Management of Colorectal Cancer

  • Practical Pharmacogenomics
  • Published:
American Journal of Pharmacogenomics

Abstract

The prognosis of patients with colorectal cancer is impacted by various factors at the time of diagnosis, including location of the tumor, gender, age and overall performance status of the patient. Optimal postoperative management of patients who have undergone successful tumor resection involves the utilization of reliable determninants of prognosis to help select patients who would benefit from adjuvant treatment, while sparing others from drug-related adverse effects. Tailoring chemotherapy for patients with disseminated cancer, or for patients who receive adjuvant chemotherapy, is also critical.

Interpatient differences in tumor response and drug toxicity are common during chemotherapy. Genomic variability of key metabolic enzyme complexes, drug targets, and drug transport molecules is an important contributing factor. The identification of genetic markers of response and prognosis will aid in the development of more individualized chemotherapuetic strategies for cancer patients. Potential prognostic indicators in colorectal cancer include oncogenes, tumor suppressor genes, genes involved in angiogenic and apoptotic pathways and cell proliferation, and those encoding targets of chemotherapy. Specifically, molecular markers such as deletion of 18q (DCC), p27 and microsatellite instability are promising as indicators of good or poor prognosis.

Molecular determinants of efficacy and host toxicity of the most commonly used drugs in colorectal cancer, fluoracil, irinotecan and oxaliplatin, are being investigated. Alterations in gene expression, protein expression and polymorphic variants in genes encoding thymidylate synthase, dihydropyrimidine dehydrogenase, dUTP nucleotidehydrolase and thymidine phosphorylase (for fluoropyrimidine-based chemotherapy), uridine diphosphate glucosyltransferase (UGT) 1A1 and carboxylesterase (for irinotecan therapy), and excision repair cross-complementing genes (ERCC1 and ERCC2) and glutathione-S-transferase P1 (for oxalilplatin-based regimens) may be useful as markers for clinical drug response, survival and host toxicity.

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Notes

  1. 1Dukes’ stage A = tumor confined to bowel wall; B = tumor extending through bowel wall; C = lymph node metastases; Duke modified Astler-Coller classification (MAC) stage D = distant metastases.

References

  1. Midgley R, Kerr D. Colorectal cancer. Lancet 1999; 353: 391–9

    Article  PubMed  CAS  Google Scholar 

  2. Hermanek P, Wiebelt H, Staimmer D, et al. Prognostic factors of rectum carcinoma: experience of the German Multicentre Study SGCRC: German Study Group Colo-Rectal Carcinoma. Tumori 1995; 81: 60–4

    PubMed  CAS  Google Scholar 

  3. Wolmark N, Wieand HS, Rockette HE, et al. The prognostic significance of tumor location and bowel obstruction in Dukes B and C colorectal cancer: findings from the NSABP clinical trials. Ann Surg 1983; 198: 743–52

    Article  PubMed  CAS  Google Scholar 

  4. McArdle CS, Hole D. Impact of variability among surgeons on postoperative morbidity and mortality and ultimate survival. BMJ 1991; 302: 1501–5

    Article  PubMed  CAS  Google Scholar 

  5. McLeod HL, Murray GI. Tumour markers of prognosis in colorectal cancer. Br J Cancer 1999; 79: 191–203

    Article  PubMed  CAS  Google Scholar 

  6. Keino-Masu K, Masu M, Hinck L, et al. Deleted in colorectal cancer (DCC) encodes a netrin receptor. Cell 1996; 87: 175–85

    Article  PubMed  CAS  Google Scholar 

  7. Chan SS, Zheng H, Su MW, et al. UNC-40, a C. elegans homolog of DCC (deleted in colorectal cancer), is required in motile cells responding to UNC-6 netrin cues. Cell 1996; 87: 187–95

    Article  PubMed  CAS  Google Scholar 

  8. Mehlen P, Rabizadeh S, Snipas SJ, et al. The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis. Nature 1998; 395: 801–4

    Article  PubMed  CAS  Google Scholar 

  9. Jen J, Kim H, Piantadosi S, et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 1994; 331: 213–21

    Article  PubMed  CAS  Google Scholar 

  10. Shibata D, Reale MA, Lavin P, et al. The DCC protein and prognosis in colorectal cancer. N Engl J Med 1996; 335: 1727–32

    Article  PubMed  CAS  Google Scholar 

  11. Martinez-Lopez E, Abad A, Font A, et al. Allelic loss on chromosome 18q as a prognostic marker in stage II colorectal cancer. Gastroenterology 1998; 114: 1180–7

    Article  PubMed  CAS  Google Scholar 

  12. Watanabe T, Wu TT, Catalano PJ, et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 2001; 344: 1196–206

    Article  PubMed  CAS  Google Scholar 

  13. Steeg PS, Abrams JS. Cancer prognostics: past, present and p27. Nat Med 1997; 3: 152–4

    Article  PubMed  CAS  Google Scholar 

  14. Thomas GV, Szigeti K, Murphy M, et al. Down-regulation of p27 is associated with development of colorectal adenocarcinoma metastases. Am J Pathol 1998; 153: 681–7

    Article  PubMed  CAS  Google Scholar 

  15. Loda M, Cukor B, Tam SW, et al. Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med 1997; 3: 231–4

    Article  PubMed  CAS  Google Scholar 

  16. Yao J, Eu KW, Seow-Choen F, et al. Down-regulation of p27 is a significant predictor of poor overall survival and may facilitate metastasis in colorectal carcinomas. Int J Cancer 2000; 89: 213–6

    Article  PubMed  CAS  Google Scholar 

  17. Palmqvist R, Stenling R, Oberg A, et al. Prognostic significance of p27(Kipl) expression in colorectal cancer: a clinico-pathological characterization. J Pathol 1999; 188: 18–23

    Article  PubMed  CAS  Google Scholar 

  18. Fredersdorf S, Burns J, Milne AM, et al. High level expression of p27(kip1) and cyclin D1 in some human breast cancer cells: inverse correlation between the expression of p27(kip1) and degree of malignancy in human breast and colorectal cancers. Proc Natl Acad Sci U S A 1997; 4: 6380–5

    Article  Google Scholar 

  19. Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science 1993; 260: 816–9

    Article  PubMed  CAS  Google Scholar 

  20. Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A 1998; 95: 6870–5

    Article  PubMed  CAS  Google Scholar 

  21. Lothe RA, Peltomaki P, Meling GI, et al. Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res 1993; 53: 5849–52

    PubMed  CAS  Google Scholar 

  22. Bubb VJ, Curtis LJ, Cunningham C, et al. Microsatellite instability and the role of hMSH2 in sporadic colorectal cancer. Oncogene 1996; 12: 2641–9

    PubMed  CAS  Google Scholar 

  23. Gryfe R, Kim H, Hsieh ET, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 2000; 342: 69–77

    Article  PubMed  CAS  Google Scholar 

  24. Hailing KC, French AJ, McDonnell SK, et al. Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J Natl Cancer Inst 1999; 91: 1295–303

    Article  Google Scholar 

  25. Hemminki A, Mecklin JP, Jarvinen H, et al. Microsatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy. Gastroenterology 2000; 119: 921–8

    Article  PubMed  CAS  Google Scholar 

  26. Feeley KM, Fullard JF, Heneghan MA, et al. Microsatellite instability in sporadic colorectal carcinoma is not an indicator of prognosis. J Pathol 1999; 188: 14–7

    Article  PubMed  CAS  Google Scholar 

  27. Salahshor S, Kressner U, Fischer H, et al. Microsatellite instability in sporadic colorectal cancer is not an independent prognostic factor. Br J Cancer 1999; 81: 190–3

    Article  PubMed  CAS  Google Scholar 

  28. Cox LS, Lane DP. Tumour suppressors, kinases and clamps: how p53 regulates the cell cycle in response to DNA damage. Bioessays 1995; 17: 501–8

    Article  PubMed  CAS  Google Scholar 

  29. Wynford-Thomas D. P53 in tumour pathology: can we trust immunocytochemistry? J Pathol 1992; 166: 329–30

    Article  PubMed  CAS  Google Scholar 

  30. Russo A, Migliavacca M, Zanna I, et al. p53 Mutations in the L3-loop zinc-binding domain, DNA-ploidy, and S phase fraction are independent prognostic indicators in colorectal cancer: a prospective study with a five-year follow-up. Cancer Epidemiol Biomarkers Prev 2002; 11: 1322–31

    PubMed  CAS  Google Scholar 

  31. Borresen-Dale A, Lothe RA, Meling GI. TP53 and long term prognosis in colorectal cancer: mutations in the L3 zinc-binding domain predict poor survival. Clin Cancer Res 1998; 4: 203–10

    PubMed  CAS  Google Scholar 

  32. Goh H, Chan C, Khine K. p53 and behavior of colorectal cancer. Lancet 1994; 344: 233–4

    Article  PubMed  CAS  Google Scholar 

  33. Aas T, Borresen A, Geisler S. Specific p53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med 1996; 2: 811–3

    Article  PubMed  CAS  Google Scholar 

  34. Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999; 286: 487–91

    Article  PubMed  CAS  Google Scholar 

  35. Lima JJ, Thomason DB, Mohamed MH, et al. Impact of genetic polymorphisms of the beta2-adrenergic receptor on albuterol bronchodilator pharmacodynamics. Clin Pharmacol Ther 1999; 65: 519–25

    Article  PubMed  CAS  Google Scholar 

  36. Gebhardt F, Zanker KS, Brandt B. Modulation of epidermal growth factor receptor gene transcription by a polymorphic dinucleotide repeat in intron 1. J Biol Chem 1999; 274: 13176–80

    Article  PubMed  CAS  Google Scholar 

  37. Ando Y, Saka H, Ando M, et al. Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res 2000; 60: 6921–6

    PubMed  CAS  Google Scholar 

  38. Van Kuilenburg AB, Vreken P, Beex LV, et al. Heterozygosity for a point mutation in an invariant splice donor site of dihydropyrimidine dehydrogenase and severe 5-fluorouracil related toxicity. Eur J Cancer 1997; 33: 2258–64

    Article  PubMed  Google Scholar 

  39. Park DJ, Stoehlmacher J, Zhang W, et al. A Xeroderma pigmentosum group D gene polymorphism predicts clinical outcome to platinum-based chemotherapy in patients with advanced colorectal cancer. Cancer Res 2001; 61: 8654–8

    PubMed  CAS  Google Scholar 

  40. Kundu NG, Heidelberger C. Cyclopenta(f)isoquinoline derivatives designed to bind specifically to native deoxyribonucleic acid: 3. Interaction of 6-carbamylmethyl-8-methyl-7H-cyclopenta(f)isoquinolin-3(2H)-one with deoxyribonucleic acids and polydeoxyribonucleotides. Biochem Biophys Res Commun 1974; 60: 561–8

    Article  PubMed  CAS  Google Scholar 

  41. Danenberg PV. Thymidylate synthetase: a target enzyme in cancer chemotherapy. Biochim Biophys Acta 1977; 473: 73–92

    PubMed  CAS  Google Scholar 

  42. Leichman CG, Lenz HJ, Leichman L, et al. Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin. J Clin Oncol 1997; 15: 3223–9

    PubMed  CAS  Google Scholar 

  43. Shirota Y, Stoehlmacher J, Brabender J, et al. ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol 2001; 19: 4298–304

    PubMed  CAS  Google Scholar 

  44. Sugiyama Y, Sugiyama K, Hirai Y, et al. Microdissection is essential for gene expression profiling of clinically resected cancer tissues. Am J Clin Pathol 2002; 117: 109–16

    Article  PubMed  CAS  Google Scholar 

  45. Fink L, Kohlhoff S, Stein MM, et al. cDNA array hybridization after laser-assisted microdissection from nonneoplastic tissue. Am J Pathol 2002; 160: 81–90

    Article  PubMed  CAS  Google Scholar 

  46. Miyamoto S, Ochiai A, Boku N, et al. Discrepancies between the gene expression, protein expression, and enzymatic activity of thymidylate synthase and dihydropyrimidine dehydrogenase in human gastrointestinal cancers and adjacent normal mucosa. Int J Oncol 2001; 18: 705–13

    PubMed  CAS  Google Scholar 

  47. Salonga D, Danenberg KD, Johnson M, et al. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res 2000; 6: 1322–7

    PubMed  CAS  Google Scholar 

  48. Danenberg K, Hollywood E, Shirota J, et al. Thymidylate synthase gene expression levels in primary colorectal tumors correlate with those in matched metastases [abstract 1722]. Proc Am Soc Clin Oncol 2001; 20: 431A

    Google Scholar 

  49. Ichikawa W, Yamada H, Uetake H, et al. Difference of thymidylate synthase gene expression in primary colorectal cancer and various metastatic sites [abstract 601]. Proc Am Soc Clin Oncol 2001; 20

  50. Kaneda S, Takeishi K, Ayusawa D, et al. Role in translation of a triple tandemly repeated sequence in the 5’-untranslated region of human thymidylate synthase mRNA. Nucleic Acids Res 1987; 15: 1259–70

    Article  PubMed  CAS  Google Scholar 

  51. Horie N, Aiba H, Oguro K, et al. Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct 1995; 20: 191–7

    Article  PubMed  CAS  Google Scholar 

  52. Kawakami K, Salonga D, Park JM, et al. Different lengths of a polymorphic repeat sequence in the thymidylate synthase gene affect translational efficiency but not its gene expression. Clin Cancer Res 2001; 7: 4096–101

    PubMed  CAS  Google Scholar 

  53. Luo HR, Lu XM, Yao YG, et al. Length polymorphism of thymidylate synthase regulatory region in Chinese populations and evolution of the novel alleles. Biochem Genet 2002; 40: 41–51

    Article  PubMed  CAS  Google Scholar 

  54. Marsh S, Collie-Duguid ES, Li T, et al. Ethnic variation in the thymidylate synthase enhancer region polymorphism among Caucasian and Asian populations. Genomics 1999; 58: 310–2

    Article  PubMed  CAS  Google Scholar 

  55. Marsh S, Ameyaw MM, Githang’a J, et al. Novel thymidylate synthase enhancer region alleles in African populations [letter]. Hum Mutat 2000; 16: 528

    Article  PubMed  CAS  Google Scholar 

  56. Pullarkat ST, Stoehlmacher J, Ghaderi V, et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J 2001; 1: 65–70

    Article  PubMed  CAS  Google Scholar 

  57. Kawakami K, Omura K, Kanehira E, et al. Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res 1999; 19: 3249–52

    PubMed  CAS  Google Scholar 

  58. Marsh S, McKay JA, Cassidy J, et al. Polymorphism in the thymidylate synthase promoter enhancer region in colorectal cancer. Int J Oncol 2001; 19: 383–6

    PubMed  CAS  Google Scholar 

  59. Iacopetta B, Grieu F, Joseph D, et al. A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil. Br J Cancer 2001; 85: 827–30

    Article  PubMed  CAS  Google Scholar 

  60. Etienne MC, Chazal M, Laurent-Puig P, et al. Prognostic value of tumoral thymidylate synthase and p53 in metastatic colorectal cancer patients receiving fluorouracil-based chemotherapy: phenotypic and genotypic analyses. J Clin Oncol 2002; 20: 2832–43

    Article  PubMed  CAS  Google Scholar 

  61. Villafranca E, Okruzhnov Y, Dominguez MA, et al. Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer. J Clin Oncol 2001; 19: 1779–86

    PubMed  CAS  Google Scholar 

  62. Lu B, Gil B, Zhang W, et al. Thymidylate synthase polymorphism predicts pelvic recurrence in rectal cancer patients treated with combined modalities [abstract 2237]. Proc Am Soc Clin Oncol 2002; 21: 106B

    Google Scholar 

  63. Ulrich CM, Bigler J, Velicer CM, et al. Searching expressed sequence tag databases: discovery and confirmation of a common polymorphism in the thymidylate synthase gene. Cancer Epidemiol Biomarkers Prev 2000; 9:1381–5

    PubMed  CAS  Google Scholar 

  64. Rajagopalan LE, Malter JS. Growth factor-mediated stabilization of amyloid precursor protein mRNA is mediated by a conserved 29-nucleotide sequence in the 3′-untranslated region. J Neurochem 2000; 74: 52–9

    Article  PubMed  CAS  Google Scholar 

  65. Gou Q, Liu CH, Ben-Av P, et al. Dissociation of basal turnover and cytokineinduced transcript stabilization of the human cyclooxygenase-2 mRNA by mutagenesis of the 3′-untranslated region. Biochem Biophys Res Commun 1998; 242: 508–12

    Article  PubMed  CAS  Google Scholar 

  66. Lenz H-J, Zhang W, Zahedy S. A 6 base-pair deletion in the 3′UTR of the thymidylate synthase gene predicts TS mRNA expression in colorectal cancer: a possible candidate gene for colorectal cancer risk [abstract 1591]. Proc Am Soc Cancer Res 2002; 43

  67. Lenz H-J, Park DJ, Zhang W, et al. A multivariate analysis of genetic markers for clinical response to 5-FU/oxaliplatin chemotherapy in advanced colorectal cancer [abstract 513]. Proc Am Soc Clin Oncol 2002; 21: 129A

    Google Scholar 

  68. Aschele C, Debernardis D, Casazza S, et al. Immunohistochemical quantitation of thymidylate synthase expression in colorectal cancer metastases predicts for clinical outcome to fluorouracil-based chemotherapy. J Clin Oncol 1999; 17: 1760–70

    PubMed  CAS  Google Scholar 

  69. Cascinu S, Aschele C, Barni S, et al. Thymidylate synthase protein expression in advanced colon cancer: correlation with the site of metastasis and the clinical response to leucovorin-modulated bolus 5-fluorouracil. Clin Cancer Res 1999; 5: 1996–9

    PubMed  CAS  Google Scholar 

  70. Davies MM, Johnston PG, Kaur S, et al. Colorectal liver metastasis thymidylate synthase staining correlates with response to hepatic arterial floxuridine. Clin Cancer Res 1999; 5: 325–8

    PubMed  CAS  Google Scholar 

  71. Johnston PG, Lenz HJ, Leichman CG, et al. Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res 1995; 55: 1407–12

    PubMed  CAS  Google Scholar 

  72. Aschele C, Debernardis D, Tunesi G, et al. Thymidylate synthase protein expression in primary colorectal cancer compared with the corresponding distant metastases and relationship with the clinical response to 5-fluorouracil. Clin Cancer Res 2000; 6: 4797–802

    PubMed  CAS  Google Scholar 

  73. Findlay MP, Cunningham D, Morgan G, et al. Lack of correlation between thymidylate synthase levels in primary colorectal tumours and subsequent response to chemotherapy. Br J Cancer 1997; 75: 903–9

    Article  PubMed  CAS  Google Scholar 

  74. Allegra CJ, Parr AL, Wold LE, et al. Investigation of the prognostic and predictive value of thymidylate synthase, p53, and Ki-67 in patients with locally advanced colon cancer. J Clin Oncol 2002; 20: 1735–43

    Article  PubMed  CAS  Google Scholar 

  75. Edler D, Glimelius B, Hallstrom M, et al. Thymidylate synthase expression in colorectal cancer: a prognostic and predictive marker of benefit from adjuvant fluorouracil-based chemotherapy. J Clin Oncol 2002; 20: 1721–8

    Article  PubMed  CAS  Google Scholar 

  76. Iltzsch MH, el Kouni MH, Cha S. Kinetic studies of thymidine phosphorylase from mouse liver. Biochemistry 1985; 24: 6799–807

    Article  PubMed  CAS  Google Scholar 

  77. Heggie GD, Sommadossi JP, Cross DS, et al. Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. Cancer Res 1987; 47: 2203–6

    PubMed  CAS  Google Scholar 

  78. Leichman L, Lenz HJ, Leichman CG, et al. Quantitation of intratumoral thymidylate synthase expression predicts for resistance to protracted infusion of 5-fluorouracil and weekly leucovorin in disseminated colorectal cancers: preliminary report from an ongoing trial. Eur J Cancer 1995; 1A: 1306–10

    Article  Google Scholar 

  79. Metzger R, Danenberg K, Leichman CG, et al. High basal level gene expression of thymidine phosphorylase (platelet-derived endothelial cell growth factor) in colorectal tumors is associated with nonresponse to 5-fluorouracil. Clin Cancer Res 1998; 4: 2371–6

    PubMed  CAS  Google Scholar 

  80. Takebayashi Y, Akiyama S, Akiba S, et al. Clinicopathologic and prognostic significance of an angiogenic factor, thymidine phosphorylase, in human colorectal carcinoma. J Natl Cancer Inst 1996; 88: 1110–7

    Article  PubMed  CAS  Google Scholar 

  81. Lu Z, Zhang R, Diasio RB. Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy. Cancer Res 1993; 53: 5433–8

    PubMed  CAS  Google Scholar 

  82. Etienne MC, Lagrange JL, Dassonville O, et al. Population study of dihydropyrimidine dehydrogenase in cancer patients. J Clin Oncol 1994; 12: 2248–53

    PubMed  CAS  Google Scholar 

  83. McLeod HL, Collie-Duguid ES, Vreken P, et al. Nomenclature for human DPYD alleles. Pharmacogenetics 1998; 8: 455–9

    Article  PubMed  CAS  Google Scholar 

  84. Diasio RB, Beavers TL, Carpenter JT. Familial deficiency of dihydropyrimidine dehydrogenase: biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity. J Clin Invest 1988; 81: 47–51

    Article  PubMed  CAS  Google Scholar 

  85. Johnson MR, Hageboutros A, Wang K, et al. Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil. Clin Cancer Res 1999; 5: 2006–11

    PubMed  CAS  Google Scholar 

  86. van Kuilenburg AB, Muller EW, Haasjes J, et al. Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: frequency of the common IVS14+1G>A mutation causing DPD deficiency. Clin Cancer Res 2001; 7(5): 1149–53

    PubMed  Google Scholar 

  87. van Kuilenburg AB, Vreken P, Abeling NG, et al. Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. Hum Genet 1999; 104:1–9

    Article  PubMed  Google Scholar 

  88. Takenoue T, Kitayama J, Takei Y, et al. Characterization of dihydropyrimidine dehydrogenase on immunohistochemistry in colon carcinoma, and correlation between immunohistochemical score and protein level or messenger RNA expression. Ann Oncol 2000; 11: 273–9

    Article  PubMed  CAS  Google Scholar 

  89. Nishimura G, Terada I, Kobayashi T, et al. Thymidine phosphorylase and dihydropyrimidine dehydrogenase levels in primary colorectal cancer show a relationship to clinical effects of 5′-deoxy-5-fluorouridine as adjuvant chemotherapy. Oncol Rep 2002; 9: 479–82

    PubMed  CAS  Google Scholar 

  90. Ladner RD, Lynch FJ, Groshen S, et al. dUTP nucleotidohydrolase isoform expression in normal and neoplastic tissues: association with survival and response to 5-fluorouracil in colorectal cancer. Cancer Res 2000; 60: 3493–503

    PubMed  CAS  Google Scholar 

  91. Ladner RD. The role of dUTPase and uracil-DNA repair in cancer chemotherapy. Curr Protein Pept Sci 2001; 2: 361–70

    Article  PubMed  CAS  Google Scholar 

  92. Chen AY, Liu LF. Mechanisms of resistance of topoisomerase inhibitors. Cancer Treat Res 1994; 73: 263–81

    Article  PubMed  CAS  Google Scholar 

  93. Dennis MJ, Bijnen JH, Grochow LB, et al. An overview of the clinical pharmacology of topotecan. Semin Oncol 1997; 24Suppl. 5: 12–8

    Google Scholar 

  94. Eng WK, Faucette L, Johnson RK, et al. Evidence that topoisomerase 1 is necessary for the cytotoxic effects of camptothecin. Mol Pharmacol 1988; 34: 755–60

    PubMed  CAS  Google Scholar 

  95. Hsiang YH, Liu LF. Identification of mammalian DNA topoisomerase 1 as an intracellular target of the anticancer drug camptothecin. Cancer Res 1988; 48: 1722–6

    PubMed  CAS  Google Scholar 

  96. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan Study Group. N Engl J Med 2000; 343: 905–14

    Article  PubMed  CAS  Google Scholar 

  97. Andre T, Bensmaine MA, Louvet C, et al. Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol 1999; 17: 3560–8

    PubMed  CAS  Google Scholar 

  98. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 2938–47

    PubMed  Google Scholar 

  99. Prewett MC, Hooper AT, Bassi R, et al. Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res 2002; 8: 994–1003

    PubMed  CAS  Google Scholar 

  100. Iyer L, King CD, Whitington PF, et al. Genetic predisposition to the metabolism of irinotecan (CPT-11): role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 1998; 101: 847–54

    Article  PubMed  CAS  Google Scholar 

  101. Innocenti F, Iyer L, Ratain MJ. Pharmacogenetics of anticancer agents: lessons from amonafide and irinotecan. Drug Metab Dispos 2001; 29: 596–600

    PubMed  CAS  Google Scholar 

  102. Iyer L, Das S, Janisch L, et al. UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J 2002; 2: 43–7

    Article  PubMed  CAS  Google Scholar 

  103. Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 1995; 333: 1171–5

    Article  PubMed  CAS  Google Scholar 

  104. Iyer L, Hall D, Das S, et al. Phenotype-genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism. Clin Pharmacol Ther 1999; 65: 576–82

    Article  PubMed  CAS  Google Scholar 

  105. Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A 1998; 95: 8170–4

    Article  PubMed  CAS  Google Scholar 

  106. Yamamoto K, Sato H, Fujiyama Y, et al. Contribution of two missense mutations (G71R and Y486D) of the bilirubin UDP glycosyltransferase (UGT1A1) gene to phenotypes of Gilbert’s syndrome and Crigler-Najjar syndrome type II. Biochim Biophys Acta 1998; 1406: 267–73

    Article  PubMed  CAS  Google Scholar 

  107. Monaghan G, Ryan M, Seddon R, et al. Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert’s syndrome. Lancet 1996; 347: 578–81

    Article  PubMed  CAS  Google Scholar 

  108. Iyer L, Janisch L, Das S, et al. UGT1A1 promotor genotype correlates with pharmacokinetics of irinotecan [abstract 690]. Proc Am Soc Clin Oncol 2000; 19: 171

    Google Scholar 

  109. Aono S, Adachi Y, Uyama E, et al. Analysis of genes for bilirubin UDP-glucuronosyltransferase in Gilbert’s syndrome. Lancet 1995; 345: 958–9

    Article  PubMed  CAS  Google Scholar 

  110. Haaz MC, Rivory L, Riche C, et al. Metabolism of irinotecan (CPT-11) by human hepatic microsomes: participation of cytochrome P-450 3A and drug interactions. Cancer Res 1998; 58: 468–72

    PubMed  CAS  Google Scholar 

  111. Haaz MC, Riche C, Rivory LP, et al. Biosynthesis of an aminopiperidino metabolite of irinotecan [7-ethyl-10-[4-(l-piperidino)-l-piperidino-]carbonyloxycamptothecine] by human hepatic microsomes. Drug Metab Dispos 1998; 26: 769–74

    PubMed  CAS  Google Scholar 

  112. Rivory LP, Riou JF, Haaz MC, et al. Identification and properties of a major plasma metabolite of irinotecan (CPT-11) isolated from the plasma of patients. Cancer Res 1996; 56: 3689–94

    PubMed  CAS  Google Scholar 

  113. Rebbeck TR, Jaffe JM, Walker AH, et al. Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 1998; 90: 1225–9

    Article  PubMed  CAS  Google Scholar 

  114. Kawato Y, Furuta T, Aonuma M, et al. Antitumor activity of a camptothecin derivative, CPT-11, against human tumor xenografts in nude mice. Cancer Chemother Pharmacol 1991; 28: 192–8

    Article  PubMed  CAS  Google Scholar 

  115. Humerickhouse R, Lohrbach K, Li L, et al. Characterization of CPT-11 hydrolysis by human liver carboxylesterase isoforms hCE-1 and hCE-2. Cancer Res 2000; 60: 1189–92

    PubMed  CAS  Google Scholar 

  116. Khanna R, Morton CL, Danks MK, et al. Proficient metabolism of irinotecan by a human intestinal carboxylesterase. Cancer Res 2000; 60: 4725–8

    PubMed  CAS  Google Scholar 

  117. Goldberg RM, Morton RF, Sargent DJ, et al. N9741: oxaliplatin (oxal) or CPT-11 + 5-fluorouracil (5FU)/leucovorin (LV) or oxal + CPT-11 in advanced colorectal cancer (CRC): initial toxicity and response data from a GI Intergroup study [abstract 511]. Proc Am Soc Clin Oncol 2002; 21: 128A

    Google Scholar 

  118. Schmoll HJ, Cassidy J. Integrating oxaliplatin into the management of colorectal cancer. Oncologist 2001; 6Suppl. 4: 24–8

    Article  PubMed  CAS  Google Scholar 

  119. Hoeijmakers JH. Nucleotide excision repair. II: from yeast to mammals. Trends Genet 1993; 9: 211–7

    Article  PubMed  CAS  Google Scholar 

  120. Van Houten B. Nucleotide excision repair in Escherichia coli. Microbiol Rev 1990; 54: 18–51

    PubMed  Google Scholar 

  121. Board PG, Baker RT, Chelvanayagam G, et al. Zeta, a novel class of glutathione transferases in a range of species from plants to humans. Biochem J 1998; 328: 929–35

    Google Scholar 

  122. Moscow JA, Fairchild CR, Madden MJ, et al. Expression of anionic glutathione S-transferases and P-glycoprotein genes in human tissues and tumors. Cancer Res 1989; 49: 1422–8

    PubMed  CAS  Google Scholar 

  123. Tsuchida S, Sato K. Glutathione transferases and cancer. Crit Rev Biochem Mol Biol 1993; 27: 337–87

    Article  Google Scholar 

  124. Hoban PR, Robson CN, Davies SM, et al. Reduced topoisomerase II and elevated alpha class glutathione S-transferase expression in a multidrug resistant CHO cell line highly cross-resistant to mitomycin C. Biochem Pharmacol 1992; 43: 685–93

    Article  PubMed  CAS  Google Scholar 

  125. Chao CC, Huang YT, Ma CM, et al. Overexpression of gluthathione S-transferase and elevation of thiol pools in multi-drug resistant human colon cancer cell line. Mol Pharmacol 1992; 41: 69–75

    PubMed  CAS  Google Scholar 

  126. Goto S, Iida T, Cho S, et al. Overexpression of glutathione S-transferase pi enhances the adduct formation of cisplatin with glutathione in human cancer cells. Free Radic Res 1999; 31: 549–58

    Article  PubMed  CAS  Google Scholar 

  127. Ban N, Takahashi Y, Takayama T, et al. Transfection of glutathione S-transferase (GST)-pi antisense complementary DNA increases the sensitivity of a colon cancer cell line to adriamycin, cisplatin, melphalan and etoposide. Cancer Res 1996; 56: 3577–82

    PubMed  CAS  Google Scholar 

  128. Zimniak P, Nanduri B, Pikula S, et al. Naturally occurring human glutathione S-transferase GST-P1 isoforms with isoleucine and valine in position 104 differ in enzymatic properties. Eur J Biochem 1994; 224: 893–9

    Article  PubMed  CAS  Google Scholar 

  129. Watson MA, Stewart RK, Smith GB, et al. Human glutathione S-transferase P1 polymorphisms: relationship to lung tissue enzyme activity and population frequency distribution. Carcinogenesis 1998; 19: 275–80

    Article  PubMed  CAS  Google Scholar 

  130. Srivastava SK, Singhal SS, Hu X, et al. Differential catalytic efficiency of allelic variants of human glutathione S-transferase Pi in catalyzing the glutathione conjugation of thiotepa. Arch Biochem Biophys 1999; 366: 89–94

    Article  PubMed  CAS  Google Scholar 

  131. Johansson AS, Sternberg G, Widersten M, et al. Structure-activity relationships and thermal stability of human glutathione transferase P1-1 governed by the Hsite residue 105. J Mol Biol 1998; 278: 687–98

    Article  PubMed  CAS  Google Scholar 

  132. Stoehlmacher J, Park DJ, Zhang W, et al. Association between glutathione S-transferase P1, T1, and M1 genetic polymorphism and survival of patients with metastatic colorectal cancer. J Natl Cancer Inst 2002; 94: 936–42

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors work was supported by grants (R01 CA 82655, K24 CA82754, and P30 CA14089).

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  1. Division of Medical Oncology, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Suite 3456, Los Angeles, California, 90033, USA

    Jan Stoehlmacher &  Heinz-Josef Lenz

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Correspondence to Heinz-Josef Lenz.

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Stoehlmacher, J., Lenz, HJ. Implications of Genetic Testing in the Management of Colorectal Cancer. Am J Pharmacogenomics 3, 73–88 (2003). https://doi.org/10.2165/00129785-200303020-00001

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