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Determinants of prognosis and response to therapy in colorectal cancer

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Abstract

Identification of the molecular determinants of 5-fluorouracil (5-FU) and irinotecan (CPT-11) efficacy and toxicity is critically important for the development of more efficient and less toxic treatment strategies for patients with colon cancer. We have identified molecular predictors of response to chemotherapy with 5-FU and survival in patients with advanced colorectal cancer. Low gene expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) are associated with response and survival. Preliminary data suggest that gene expression levels of topoisomerase I, p21, bcl-2, and ICE may be predictive of response to therapy with CPT-11. Increased toxicity seen in patients treated with CPT-11 may be explained by polymorphism in the UGT1A1 gene, which is responsible for glucuronidation of the active metabolite of CPT-11.

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References and Recommended Reading

  1. Greenlee RT, Murray T, Bolden S, Wingo PA: Cancer statistics 2000. CA Cancer J Clin 2000, 50:7–33.

    PubMed  CAS  Google Scholar 

  2. Miller BA, Gloeckler-Ries LA, Hankey BF, et al.: Cancer Statistics Review: 1973–1989. Bethesda, MD: National Institutes of Health; 1993; NIH Publication 92-2789.

    Google Scholar 

  3. Moertel CG: Chemotherapy for colorectal cancer. N Engl J Med 1994, 330:1136–1143.

    Article  PubMed  CAS  Google Scholar 

  4. Grem JL: 5-Fluorouracil plus leucovorin in cancer therapy. In Principles and Practice of Oncology Update, series 2, no. 7. Edited by DeVita VT Jr, Hellman S, Rosenberg SA. Philadelphia: JB Lippincott; 1988.

    Google Scholar 

  5. Berger SH, Jeng C-H, Johnson LF, Berger FG: Thymidylate synthase overproduction and gene amplification in fluorodeoxyuridine-resistant human cells. Mol Pharmacol 1985, 28:461–467.

    PubMed  CAS  Google Scholar 

  6. Danenberg KD, Danenberg PV: Activity of thymidylate synthase and its inhibition by 5-fluorouracil in highly enzyme-overproducing cells resistant to 10-propargyl-5, 8-dideazafolate. Mol Pharmacol 1989, 36:219–223.

    PubMed  CAS  Google Scholar 

  7. Spears CP, Gustavson BG, Berne M, et al.: Mechanism of innate resistance to thymidylate synthase inhibition after 5-fluorouracil. Cancer Res 1988, 48:5894–5900.

    PubMed  CAS  Google Scholar 

  8. Lenz H-J, Leichman CG, Danenberg KD, et al.: Thymidylate synthase expression in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival. J Clin Oncol 1996, 14:176–182.

    PubMed  CAS  Google Scholar 

  9. Leichman L, Lenz H-J, Leichman CG, et al.: Quantitation of intratumural 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, 31:1306–1310.

    Article  Google Scholar 

  10. Johnston PG, Lenz H-J, Leichman CG, et al.: Thymidylate synthase protein and gene expression predicts for response to 5-fluorouracil, leucovorin in patients with colorectal and gastric cancer. Cancer Res 1995, 55:1407–1412.

    PubMed  CAS  Google Scholar 

  11. Lenz H-J, Danenberg KD, Leichman CG, et al.: P53 and thymidylate synthase expression in untreated stage II colon cancer: association with recurrence, survival and site. Clin Cancer Res 1998, 4:1227–1234.

    PubMed  CAS  Google Scholar 

  12. Lenz H-J, Kazuhiko H, Salonga D, et al.: p53 point mutations and thymidylate synthase messenger RNA levels in disseminated colorectal cancer: an analysis of response and survival. Clin Cancer Res 1998, 4:1243–1250.

    PubMed  CAS  Google Scholar 

  13. Reigner B, Verweij J, Dirix L, et al.: Effect of food on the pharmacokinetics of capecitabine and its metabolite following oral administration I cancer patients. Clin Cancer Res 1998, 4:941–948.

    PubMed  CAS  Google Scholar 

  14. Ishikawa T, Utoh M, Sawada N, Nishida M, et al.: Tumor selective delivery of 5-FU by capecitabine, a new oral fluoropyrimidine carbamate, in human cancer xenografts. Biochem Pharamcol 1998, 55:1091–1097.

    Article  CAS  Google Scholar 

  15. Sawada N, Ishikawa T, Fukase Y, Nishida M, et al.: Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by Taxol/taxotere in human cancer. Clin Cancer Res 1998, 4:1013–1019.

    PubMed  CAS  Google Scholar 

  16. Ishikawa T, Sekiguchi F, Fukase Y, Sawada N, et al.: Positive correlation between the efficacy of capecitabine and doxifluridine and the ratio of thymidine phosphorylase to dihydropyromidine dehydrogenase activities in tumors in human cancer xenografts. Cancer Res 1998, 58:685–690.

    PubMed  CAS  Google Scholar 

  17. Aschele C, Debernardis D, Casazza S, et al.: Immunohistochemical quantitaion of thymidylate synthase expression in colorectal cancer metastases predicts for clinical outcome to fluorouracilbased chemotherapy. J Clin Oncol 1999, 17:1760–1770.

    PubMed  CAS  Google Scholar 

  18. Paradiso A, Simone G, Petroni S, et al.: Thymidilate synthase and p53 primary tumour expression as predictive factors for advanced colorectal cancer patients. Br J Cancer 2000, 82:560–567.

    Article  PubMed  CAS  Google Scholar 

  19. Edler D, Kressner U, Ragnhammar P, et al.: Immunohistochemically detected thymidylate synthase in colorectal cancer: an independent prognostic factor of survival. Clin Cancer Res 2000, 6:488–492.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  21. Bjarnason GA, Lincoln D, Jordan R, et al.: Thymidylate synthase activity in human oral mucosa has a Circadian variation with peak activity during S-phase [abstract]. Proc ASCO 2000, 19:710.

    Google Scholar 

  22. Pullarkat ST, Ghaderi V, Ingles SA, et al.: Human thymidylate synthase gene polymorphism determines response to 5-FU chemotherapy [abstract]. Proc ASCO 2000, 19:942. The authors report that, in addition to TS protein or RNA expression, gene polymorphisms have been identified that may determine response to therapy. Patients with double tandem repeats have significantly higher response rates to 5-FU. This is another means to guide selection of patients most likely to respond to 5-FU therapy.

    Google Scholar 

  23. Salonga D, Danenberg M, Metzger R, 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, 6:1322–1327. This article shows that low gene expression of TP, TS, and DPD are all independent predictors of 5-FU response. Patients with low expression of all three genes had significantly longer survival than patients with a high value of any one of these gene expressions.

    PubMed  CAS  Google Scholar 

  24. Metzger R, Danenberg K, Leichman CG, et al.: High basal level gene expression of thymidine phosphorylase (plateletderived endothelial cell growth factor) in colorectal tumors is associated with nonresponse to 5-fluorouracil. Clin Cancer Res 4:2371-2376.

  25. Diasio RB, Lu Z: Dihydropyrimidine dehydrogenase activity and fluorouracil chemotherapy. J Clin Oncol 1994, 12:2239–2242.

    PubMed  CAS  Google Scholar 

  26. Diasio RB, Beavers TL, Carpenter JT: Familial deficiency of DPD: biochemical basis for familial pyrimdinemia and severe 5-FU induced toxicity. J Clin Invest 1988, 81:47–51.

    PubMed  CAS  Google Scholar 

  27. Milano G, Etienne MC, Cassuto-Viguier E, et al.: Influence of sex and age on fluorouracil clearance. J Clin Oncol 1992, 10:1171–1175.

    PubMed  CAS  Google Scholar 

  28. Lyss AP, Lilenbaum RC, Harris BE, et al.: Severe 5-FU toxicity in a patient with decreased DPD activity. Cancer Invest 1993, 11:239–240.

    PubMed  CAS  Google Scholar 

  29. Lu Z, Zhang R, Diasio RB: DPD activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients and clinical implications in 5-FU chemotherapy. Cancer Res 1993, 53:5433–5438.

    PubMed  CAS  Google Scholar 

  30. Fleming RA, Milano GA, Gaspard MH, et al.: DPD activity in cancer patients. Eur J Cancer 1993, 39A:740–744.

    Google Scholar 

  31. Danenberg K, Salonga D, Park CG, et al.: DPD and TS gene expressions identify a high percentage of colorectal tumors responding to 5-FU [abstract]. Proc ASCO 1998, 17:992.

    Google Scholar 

  32. Ishikawa Y, Kubota T, Otani Y, et al.: Dihydropyrimidine dehydrogenase and messenger RNA levels in gastric cancer possible predictor for sensitivity to 5-fluorouracil. Jpn J Cancer Res 2000, 91:105–112. The authors report that DPD protein and mRNA levels are also predictors of response in gastric cancer (ie, other GI tumors).

    PubMed  CAS  Google Scholar 

  33. Uetake H, Ichikawa W, Takechi T, et al.: Relationship between intratumoral dihydropyrimidine dehydrogenase activity and gene expression in human colorectal cancer. Clin Cancer Res 1999, 5:2836–2839.

    PubMed  CAS  Google Scholar 

  34. Saltz L, Danenberg K, Paty P, et al.: High TS expression does not preclude activity of CPT-11 in colorectal cancer [abstract]. Proc ASCO 1998, 17:1080.

    Google Scholar 

  35. Hsiang YH, Liu LF: Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 1988, 48:1722–1726.

    PubMed  CAS  Google Scholar 

  36. Irinotecan (CPT-11) Investigator’s Brochure. Bridgewater, NJ: Pharmacia & Upjohn; 1998.

  37. Gupta E, Mick R, Ramirez J, et al.: Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients. J Clin Oncol 1995, 15:1502–1510.

    Google Scholar 

  38. Rivory LP, Robert J: Identification and kinetics of betaglucuronide metabolite of SN 38 in human plasma after administration of the camptothecin derivate irinotecan. Cancer Chemother Pharmacol 1995, 36:176–179.

    PubMed  CAS  Google Scholar 

  39. Rivory LP, Haaz M-C, Canal P, et al.: Pharmacokinetic interrelationship of irinotecan (CPT-11) and its three major plasma metabolites in patients enrolled in phase I/II trials. Clin Cancer Res 1997, 3:1261–1266.

    PubMed  CAS  Google Scholar 

  40. Iyer L, King C, Tephly T, Ratain MJ: UGT isoform 1.1 (UGT1*1) glucuronidates SN 38, the active metabolite of irinotecan [abstract]. Proc ASCO 1997, 16:201A(707).

    Google Scholar 

  41. Iyer L, King CD, Whitington PF, et al.: Genetic predisposition to the metabolism of irinotecan (CPT-11): role of UGT 1AQ in the glucuronidation of its active metabolite (SN38) in human liver microsomes. J Clin Invest 1998, 101:847–854.

    Article  PubMed  CAS  Google Scholar 

  42. Iyer L, Hall D, Das S, Mortell M, et al.: Correlation with UGT1A1 versus SN38 and bilirubin glucuronidation in human liver samples [abstract]. Clin Pharmacol 1998, 63:171. Describes a way to identify those patients that may experience significant toxicity with CPT-11, allowing specific tailoring of therapy not only in terms of response but also for toxicity.

    Google Scholar 

  43. Iyer L, Janisch L, Das S, et al.: UGT1A1 promoter genotype correlates with pharmacokinetics of irinotecan (CPT-11) [abstract]. Proc ASCO 2000, 19:690.

    Google Scholar 

  44. Wasserman E, Myara A, Lokiec F, et al.: Severe CPT-11 toxicity in patients with Gilbert’s syndrome: two case reports. Ann Oncol 1997, 8:1049–1051.

    Article  PubMed  CAS  Google Scholar 

  45. Bosma PJ, Chowdhury JR, Bakker C, et al.: The genetic basis of the reduced expression of bilirubin UDP-GT 1 in Gilbert’s syndrome. N Engl J Med 1995, 33:1171–1175.

    Article  Google Scholar 

  46. Monaghan G, Ryan M, Seddon R, et al.: Genetic variation in bilirubin UDP-GT gene promoter and Gilbert’s syndrome. Lancet 1996, 347:578–581.

    Article  PubMed  CAS  Google Scholar 

  47. Sato H, Adachi Y, Koiwai O: The genetic basis of Gilbert’s syndrome. Lancet 1996, 347:557–558.

    Article  PubMed  CAS  Google Scholar 

  48. Saka H, Ando Y, Sugiura S, et al.: UGT1A1 28 pleomorphism may affect glucuronidation of SN 38 in CPT-11 chemotherapy [abstract]. Proc ASCO 1998, 17:195a.

    Google Scholar 

  49. DiRienzo A, Hall D, Iyer L, Ratain MJ: Two new alleles in the promoter of the bilirubin UDP-GT gene [abstract]. Clin Pharmacol Ther 1998, 63:207.

    Google Scholar 

  50. Lampe JW, Bigler J, Horner NK, et al.: UDP-Glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasions and Asians: relationships to serum bilirubin concentrations. Pharmacogenetics 1999, 9:341–349.

    Article  PubMed  CAS  Google Scholar 

  51. Bleiberg H, de Gramont A: Oxaliplatin plus 5-FU: clinical experience in patients with advanced colorectal cancer. Semin Oncol 1998, 25:32–39.

    PubMed  CAS  Google Scholar 

  52. Raymond E, Faivre S, Woynarowski JM, Chaney SG: Oxaliplatin: mechanism of action and antineoplastic activity. Semin Oncol 1998, 25:4–12.

    PubMed  CAS  Google Scholar 

  53. Metzger R, Leichman CG, Danenberg KD, et al.: ERCC1 MRNA levels complement TS mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and 5-fluorouracil chemotherapy. J Clin Oncol 1998, 16:309–316. This article identifies another marker that may be a predictor of response, ie, the ERCC1 gene and relative mRNA levels, which is inversely associated with response and survival and is an independent predictor of cisplatin efficacy.

    PubMed  CAS  Google Scholar 

  54. DeGramont 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, 18:2938–2947.

    CAS  Google Scholar 

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  1. Division of Medical Oncology, University of Southern California/ Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, 90033-0804, Los Angeles, CA, USA

    Syma Iqbal MD & Heinz-Josef Lenz MD

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  1. Syma Iqbal MD
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  2. Heinz-Josef Lenz MD
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Iqbal, S., Lenz, HJ. Determinants of prognosis and response to therapy in colorectal cancer. Curr Oncol Rep 3, 102–108 (2001). https://doi.org/10.1007/s11912-001-0008-5

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