Investigational New Drugs

, Volume 21, Issue 1, pp 113–129 | Cite as

Current Approaches to Novel Therapeutics in Pancreatic Cancer

  • Corina E. Akerele
  • Irina Rybalova
  • Howard L. Kaufman
  • Sridhar Mani


Pancreatic cancer is one of the most refractory neoplasms to medical treatment. Until now there has been only modest improvement in the treatment of this disease. Standards of care for combined-modality treatment of resectable as well as locally advanced, unresectable disease have not been uniformly accepted to date because of an equivocal or conflicting data. The inception of gemcitabine introduced the new era in the management of metastatic pancreatic cancer, however, new therapeutic approaches still need to be defined. The article discusses the current knowledge of the biology of this lethal disease, its impact on treatment options, and explores novel therapeutic modalities that are likely to improve outcomes and survival for patients in the future.

pancreatic cancer new therapeutic modalities 


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  1. 1.
    Greenlee RT, Murray T, Bolden S, Wingo PA: Cancer statistics. CA Cancer J Clin 50(1): 7–33, 2000Google Scholar
  2. 2.
    Brand RE, Tempero MA: Pancreatic cancer. Curr Opin Oncol 10(4): 362–366, 1998Google Scholar
  3. 3.
    Boring CC, Squires TS, Health CW Jr: Cancer statistics for African Americans. CA Cancer J Clin 42(1): 7–17, 1992Google Scholar
  4. 4.
    Schein P: Gastrointestinal cancer: A global perspective. In: Ahlgren MJ (ed.) Gastrointestinal Oncology. Lippincot, Philadelphia, PA, 1992, pp 3–11Google Scholar
  5. 5.
    Devesa SS, Blot WJ, Stone BJ, Miller BA, Tarone RE, Fraumeni JF Jr: Recent cancer trends in the United States. J Natl Cancer Inst 87(3): 175–182, 1995Google Scholar
  6. 6.
    Warshaw AL, Fernandez-del Castillo C: Pancreatic carcinoma. N Engl J Med 326(7): 455–465, 1992Google Scholar
  7. 7.
    Ahlgren JD: Epidemiology and risk factors in pancreatic cancer. Semin Oncol 23(2): 241–250, 1996Google Scholar
  8. 8.
    Michaud D, Giovannucci E, Willett W, Colditz G, Fuchs C: Coffee and alcohol consumption and the risk of pancreatic cancer in two prospective United States cohorts. Cancer Epidemiol Biomarkers Prev 10(5): 429–437, 2001Google Scholar
  9. 9.
    Kozuka S, Sassa R, Taki T, Masamoto K, Nagasawa S, Saga S, Hasegawa K, Takeuchi M: Relation of pancreatic duct hyperplasia to carcinoma. Cancer 43(4): 1418–1428, 1979Google Scholar
  10. 10.
    Yanagisawa A, Ohtake K, Ohashi K, Hori M, Kitagawa T, Sugano H, Kato Y: Frequent c-Ki-ras oncogene activation in mucous cell hyperplasias of pancreas suffering from chronic inflammation. Cancer Res 53(5): 953–956, 1993Google Scholar
  11. 11.
    Marx S, Agarwal SK, Kester MB, Heppner C, Kim YS, Skarulis MC, James LA, Goldsmith PK, Saggar SK, Park SY, Spiegel AM, Burns AL, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Emmert-Buck MR, Guru SC, Manickam P, Crabtree J, Erdos MR, Collins FS, Chandrasekharappa SC: Multiple endocrine neoplasia type 1: clinical and genetic topics. Ann Intern Med 129(6): 484–494, 1993Google Scholar
  12. 12.
    Bordi C, Brandi ML: Ductal adenocarcinoma of the pancreas in MEN-1–patients. Virchows Arch 434(4): 385–386, 1998Google Scholar
  13. 13.
    Gates LK Jr, Ulrich CD II, Whitcomb DC: Hereditary pancreatitis. Gene defects and their implications. Surg Clin North Am 79(4): 711–722, vii–viii, 1999Google Scholar
  14. 14.
    Finch MD, Howes N, Ellis I, Mountford R, Sutton R, Raraty M, Neoptolemos JP: Hereditary pancreatitis and familial pancreatic cancer. Digestion 58(6): 564–569, 1997Google Scholar
  15. 15.
    Lynch HT, Voorhees GJ, Lanspa SJ, McGreevy PS, Lynch JF: Pancreatic carcinoma and hereditary nonpolyposis colorectal cancer: a family study. Br J Cancer 52(2): 271–273, 1985Google Scholar
  16. 16.
    Neumann HP, Dinkel E, Brambs H, Wimmer B, Friedburg H, Volk B, Sigmund G, Riegler P, Haag K, Schollmeyer P et al.: Pancreatic lesions in the von Hippel-Lindau syndrome. Gastroenterology 101(2): 465–471, 1991Google Scholar
  17. 17.
    Swift M, Sholman L, Perry M, Chase C: Malignant neoplasms in the families of patients with ataxia-telangiectasia. Cancer Res 36(1): 209–215, 1976Google Scholar
  18. 18.
    Lynch HT and Fusaro RM: Pancreatic cancer and the familial atypical multiple mole melanoma (FAMMM) syndrome. Pancreas 6(2): 127–131, 1991Google Scholar
  19. 19.
    Whelan AJ, Bartsch D, Goodfellow PJ: Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. N Engl J Med 333(15): 975–977, 1995Google Scholar
  20. 20.
    Evans DB, Abbruzzese JL, Willett CG: Cancer of the pancreas. In: DeVita VT Jr, Hellman S, Rosenberg SA (eds), Cancer; Principles & Practice of Oncology, 6th edn. Lippincott Williams & Wilkins: Philadelphia, PA, 2001, pp 1126–1161Google Scholar
  21. 21.
    Moertel CG, Childs DS Jr, Reitemeier RJ, Colby MY Jr, Holbrook MA: Combined 5–fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet 2(7626): 865–867, 1969Google Scholar
  22. 22.
    Gastrointestinal Tumor Study Group: Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer 59(12): 2006–2010, 1987Google Scholar
  23. 23.
    Kalser MH, Ellenberg SS: Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 120(8): 899–903, 1985Google Scholar
  24. 24.
    Jeekel J: Adjuvant or neoadjuvant therapy for pancreatic carcinoma? Digestion 58(6): 533–535, 1997Google Scholar
  25. 25.
    van Eijck CH, Link KH, van Rossen ME, Jeekel J: (Neo) adjuvant treatment in pancreatic cancer-the need for future trials. Eur J Surg Oncol 25(2): 132–137, 1999Google Scholar
  26. 26.
    Neoptolemos JP, Dunn JA, Stocken DD: Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomized controlled trial. Lancet 358: 1576–1585, 2001Google Scholar
  27. 27.
    Abrams RA, Lillemoe KD, Piantadosi S: Continuing controversy over adjuvant therapy of pancreatic cancer. Lancet 358: 1565–1566, 2001Google Scholar
  28. 28.
    Yeo CJ, Abrams RA, Grochow LB: Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Ann Surg 225(5): 621–633, 1997Google Scholar
  29. 29.
    Hoffman JP, Weese JL, Solin LJ, Agarwal P, Engstrom P, Scher R, Paul AR, Litwin S, Watts P, Eisenberg BL: A single institutional experience with preoperative chemoradiotherapy for stage I–III pancreatic adenocarcinoma. Am Surg 59(11): 772–80; discussion 780–781, 1993Google Scholar
  30. 30.
    Spitz FR, Abbruzzese JL, Lee JE: Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol 15(3): 928–937, 1997Google Scholar
  31. 31.
    Pisters PW, Abbruzzese JL, Janjan NA, Cleary KR, Charnsangavej C, Goswitz MS, Rich TA, Raijman I, Wolff RA, Lenzi R, Lee JE, Evans DB: Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma. J Clin Oncol 16(12): 3843–3850, 1998Google Scholar
  32. 32.
    Lowy AM, Lowy AM, Lee JE, Pisters PW, Davidson BS, Fenoglio CJ, Stanford P, Jinnah R, Evans DB: Prospective, randomized trial of octreotide to prevent pancreatic fistula after pancreaticoduodenectomy for malignant disease. Ann Surg 226(5): 632–641, 1997Google Scholar
  33. 33.
    Willett CG, Lewandrowski K, Warshaw AL, Efird J, Compton CC: Resection margins in carcinoma of the head of the pancreas. Implications for radiation therapy. Ann Surg 217(2): 144–148, 1993Google Scholar
  34. 34.
    Rich TA, Evans DB: Preoperative combined modality therapy for pancreatic cancer. World J Surg 19: 264–269, 1995Google Scholar
  35. 35.
    Staley CA, Lee JE, Cleary KR, Abbruzzese JL, Fenoglio CJ, Rich TA, Evans DB: Preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for adenocarcinoma of the pancreatic head. Am J Surg 171(1): 118–124; discussion 124–125, 1996Google Scholar
  36. 36.
    Moertel CG, Frytak S, Hahn RG, O'Connell MJ, Reitemeier RJ, Rubin J, Schutt AJ, Weiland LH, Childs DS, Holbrook MA, Lavin PT, Livstone E, Spiro H, Knowlton A, Kalser M, Barkin J, Lessner H, Mann-Kaplan R, Ramming K, Douglas HO Jr, Thomas P, Nave H, Bateman J, Lokich J, Brooks J, Chaffey J, Corson JM, Zamcheck N, Novak JW: Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5–fluorouracil), and high dose radiation + 5–fluorouracil: The Gastrointestinal Tumor Study Group. Cancer 48(8): 1705–1710, 1981Google Scholar
  37. 37.
    Gastrointestinal Tumor Study Group: Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. J Natl Cancer Inst 80(10): 751–755, 1988Google Scholar
  38. 38.
    Blackstock AW, Bernard SA, Richards F, Eagle KS, Case LD, Poole ME, Savage PD, Tepper JE: Phase I trial of twice-weekly gemcitabine and concurrent radiation in patients with advanced pancreatic cancer. J Clin Oncol 17(7): 2208–2212, 1999Google Scholar
  39. 39.
    Jeekel J, Treurniet-Donker AD: Treatment perspectives in locally advanced unresectable pancreatic cancer. Br J Surg 78(11): 1332–1334, 1991Google Scholar
  40. 40.
    Roldan GE, Gunderson LL, Nagorney DM, Martin JK, Ilstrup DM, Holbrook MA, Kvols LK, McIlrath DC: External beam versus intraoperative and external beam irradiation for locally advanced pancreatic cancer. Cancer 61(6): 1110–1116, 1988Google Scholar
  41. 41.
    Garton GR, Gunderson LL, Nagorney DM, Donohue JH, Martin JK, McIlrath DC, Cha SS: High-dose preoperative external beam and intraoperative irradiation for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 27(5): 1153–1157, 1993Google Scholar
  42. 42.
    Glimelius B, Hoffman K, Sjoden PO, Jacobsson G, Sellstrom H, Enander LK, Linne T, Svensson C: Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 7(6): 593–600, 1996Google Scholar
  43. 43.
    Palmer KR, Kerr M, Knowles G, Cull A, Carter DC, Leonard RC: Chemotherapy prolongs survival in inoperable pancreatic carcinoma. Br J Surg 81(6): 882–885, 1994Google Scholar
  44. 44.
    Casper ES, Green MR, Kelsen DP, Heelan RT, Brown TD, Flombaum CD, Trochanowski B, Tarassoff PG: Phase II trial of gemcitabine (2,2′-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas. Invest New Drugs 12(1): 29–34, 1994Google Scholar
  45. 45.
    Burris HA III, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6): 2403–2413, 1997Google Scholar
  46. 46.
    Rothenberg ML, Moore MJ, Cripps MC, Andersen JS, Portenoy RK, Burris HA 3rd, Green MR, Tarassoff PG, Brown TD, Casper ES, Storniolo AM, Von Hoff DD: A phase II trial of gemcitabine in patients with 5–FU-refractory pancreas cancer. Ann Oncol 7(4): 347–353, 1996Google Scholar
  47. 47.
    Berlin J, Catalano P, Thomas J: A phase III study of gemcitabine in combination with 5–FU vs gemcitabine alone in patients with advanced pancreatic carcinoma (E2297): an Eastern Cooperative Oncology Group (ECOG) Trial. Proc Am Soc Clin Oncol 20: 127a (abstract#505), 2001Google Scholar
  48. 48.
    Maisey N, Chan I, Norman A: A randomized trial of protracted venous infusion 5–fluorouracil with or without mitomycin-C in advanced pancreatic cancer. Proc Am Soc Clin Oncol 20: 128a (abstract#507), 2001Google Scholar
  49. 49.
    Melin SA, Rocha Lima CS: Induction CPT-11 and Gemcitabine followed by twice-weekly gemcitabine and concurrent radiation for patients with unresectable pancreatic cancer. Proc Am Soc Clin Oncol ASCO 20: 147b (abstract#2337), 2001Google Scholar
  50. 50.
    Stehlin JS, Giovanella BC, Natelson EA, De Ipolyi PD, Coil D, Davis B, Wolk D, Wallace P, Trojacek A: A study of 9–nitrocamptothecin (RFS-2000) in patients with advanced pancreatic cancer. Int J Oncol 14(5): 821–831, 1999Google Scholar
  51. 51.
    D'Adamo D, Hammond L, Donehower S, Sharma S: Final result of a phase II study of DX-8951f (exatecan mesylate) in advanced pancreatic cancer. Proc Am Soc Clin Oncol 20: 134a (abstract#532), 2001Google Scholar
  52. 52.
    Philip PA, Zalupsky M.: Phase II study of gemcitabine and cisplatin in advanced or metastatic pancreatic cancer. Proc Am Soc Clin Oncol 18: 274a (abstract#1053), 1999Google Scholar
  53. 53.
    Heinemann V, Quietzsch D, Schalhorn A: Gemcitabine plus cisplatin versus gemcitabine in advanced pancreatic cancer: preliminary results of a randomized phase III trial. Proc Am Soc Clin Oncol 20: 157a (abstract#625), 2001Google Scholar
  54. 54.
    Louvet C, Andre T, de Gramont A: Gemcitabine-oxaliplatin (GEMOX) combination in advanced pancreatic carcinoma: a gercor multicenter phase II study. Proc Am Soc Clin Oncol 20: 127a (abstract#506), 2001Google Scholar
  55. 55.
    Gonzalez Cao M, Salgado E, Martin Algarra S: Docetaxel with gemcitabine in metastatic pancreatic cancer. Proc Am Soc Clin Oncol 20: 131b (abstract#2274), 2001Google Scholar
  56. 56.
    Ridwelski K, Kettner E, Lippert H: Multicenter Phase II study of weekly docetaxel and gemcitabine for the treatment of patients with advanced or recurrent pancreatic cancer. Proc Am Soc Clin Oncol 20: 157a (abstract#624), 2001Google Scholar
  57. 57.
    Moore TA, Iannitti D, Safran H: Gemcitabine, Paclitaxel and radiation for locally advanced pancreatic cancer. Proc Am Soc Clin Oncol 20: 145b (abstract#2330), 2001Google Scholar
  58. 58.
    Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, Kern SE, Hruban RH: Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 60(7): 2002–2006, 2000Google Scholar
  59. 59.
    Apple SK, Hecht JR, Lewin DN, Jahromi SA, Grody WW, Nieberg RK: Immunohistochemical evaluation of K-ras, p53, and HER-2/neu expression in hyperplastic, dysplastic, and carcinomatous lesions of the pancreas: evidence for multistep carcinogenesis. Hum Pathol 30(2): 123–129, 1999Google Scholar
  60. 60.
    Hruban RH, Wilentz RE, Kern SE: Genetic progression in the pancreatic ducts. Am J Pathol 156(6): 1821–1825, 2000Google Scholar
  61. 61.
    Brown PD, Giavazzi R: Matrix metalloproteinase inhibition: A review of anti-tumor activity. Ann Oncol 6: 967–974, 1995Google Scholar
  62. 62.
    Yamamoto H, Itoh F, Iku S, Adachi Y, Fukushima H, Sasaki S, Mukaiya M, Hirata K, Imai K: Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human pancreatic adenocarcinomas: clinicopathologic and prognostic significance of matrilysin expression. J Clin Oncol 19(4): 1118–1127, 2001Google Scholar
  63. 63.
    Gress TM, Muller-Pillasch F, Lerch MM, Friess H, Buchler M, Adler G: Expression and in-situ localization of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in pancreatic cancer. Int J Cancer 62(4): 407–413, 1995Google Scholar
  64. 64.
    Zucker S, Cao J, Chen W-T: Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene 19: 6642–6650, 2000Google Scholar
  65. 65.
    Bramhall SR, Rosemurgy A, Brown PD, Bowry C, Buckels JA: Marimastat Pancreatic Cancer Study Group: Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol 19(15): 3447–3455, 2001Google Scholar
  66. 66.
    Hess KR, Abbruzzese GL: Matrix metalloproteinase inhibition of pancreatic cancer: matching mechanism of action to clinical trial design. J Clin Oncol 19: 3445–3446, 2001Google Scholar
  67. 67.
    Moore MJ, Hamm J, Einsenberg PG, Dagenais M, Hagan K, Fields A, Greengerg B, Schwartz B, Ottaway J, Zee B, Seymour L: A comparison between gemcitabine and the matrix metalloproteinase inhibitor BAY 12–9566 in patients with advanced pancreatic cancer. Proc Am Soc Clin Oncol 19: 240a(abstract#930), 2000Google Scholar
  68. 68.
    Mangray S, King TCL: Molecular pathobiology of pancreatic adenocarcinoma. Front Biosci 3: D1148–D1160, 1998Google Scholar
  69. 69.
    Kornmann M, Ishiwata T, Itakura J, Tangvoranuntakul P, Beger HG, Korc M: Increased cyclin D1 in human pancreatic cancer is associated with decreased postoperative survival. Oncology 55(4): 363–369, 1998Google Scholar
  70. 70.
    Yamano M, Fujii H, Takagaki T, Kadowaki N, Watanabe H, Shirai T: Genetic progression and divergence in pancreatic carcinoma. Am J Pathol 156(6): 2123–2133, 2000Google Scholar
  71. 71.
    Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJ, Hruban RH, Kern SE: Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity. Am J Pathol 156(5): 1641–1651, 2000Google Scholar
  72. 72.
    Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M: Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53(4): 549–554, 1988Google Scholar
  73. 73.
    Apple SK, Hecht JR, Novak JM, Nieberg RK, Rosenthal DL, Grody WW: Polymerase chain reaction-based K-ras mutation detection of pancreatic adenocarcinoma in routine cytology smears. Am J Clin Pathol 105(3): 321–326, 1996Google Scholar
  74. 74.
    Lersch C, Van Cutsem E, Amado R, Ehninger G, Heike M, Kerr D, Rothenberg M, Baum C, Zaknoen S Randomized phase II study of SCH 66336 and gemcitabine in the treatment of metastatic adenocarcinoma of the pancreas. Proc Am Soc Clin Oncol 20: 153a(abstract#608), 2001Google Scholar
  75. 75.
    Dorr A, Bruce J, Monia B, Johnston J, Geary R, Kwoh TJ, Holmlund J, Nemunaitis J. Phase 1 and pharmacokinetic trial of ISIS 2503, a 20–Mer antisense oligonucleotide against H-RAS, by 14–day continuous infusion (CIV) in patients with advanced cancer. Proc Am Soc Clin Oncol 18: 157a (abstract#603), 1999Google Scholar
  76. 76.
    Holmlund JT, Rudin CM, Mani S, Fleming GF, Stadler W, Kunkel K, Kwoh TJ, Geary R, Dorr A, Ratain MJ: Phase I trial of ISIS 5132/ODN 698 A, a 20–Mer phosphorothioate antisense oligonucleotide inhibitor of C-RAF Kinase, administered by a 24–hour weekly intravenous infusion to patients with advanced cancer. Proc Am Soc Clin Oncol 18: 157a (abstract#605), 1999Google Scholar
  77. 77.
    Perez RP, Smith JW III, Alberts SR, Kaufman H, Posey J, Ritch P, Pipas JM, Dorr A, Holmlund J: Phase II trial of ISIS 2503, an antisense inhibitor of H-ras, in patients with advanced pancreatic carcinoma. Proc Am Soc Clin Oncol 20: 158a(abstract#628), 2001Google Scholar
  78. 78.
    Humphreys MJ, Greenhalf W, Neoptolemos JP, Ghaneh P: The potential for gene therapy in pancreatic cancer. Int J Pancreatol 26(1): 5–21, 1999Google Scholar
  79. 79.
    Shichinohe T, Senmaru N, Furuuchi K, Ogiso Y, Ishikura H, Yoshiki T, Takahashi T, Kato H, Kuzumaki N: Suppression of pancreatic cancer by the dominant negative ras mutant, N116Y. J Surg Res 66(2): 125–130, 1996Google Scholar
  80. 80.
    Hruban RH, Iacobuzio-Donahue C, Wilentz RE, Goggins M, Kern SE: Molecular pathology of pancreatic cancer. Cancer J 7(4): 251–258, 2001Google Scholar
  81. 81.
    Khleif S, Abrams S, Allegra C, Bastian A, Bergmann E, Bernstein S, Chen A, Chung Y, Hamilton JM, Kohler DR, Morrison G, Schlom J: The generation of CD4+ and CD8+ Tcell responses from patients vaccinated with mutant ras peptides corresponding to the patient's own ras mutation. Proc Am Soc Clin Oncol 16: 406a(abstract#1566), 1997Google Scholar
  82. 82.
    Wojtowicz ME, Hamilton MJ, Bernstein S, McNally D, Chatfield S, Edison M, Abrams S, Allegra CJ, Khleif SN. Clinical trial of mutant ras peptide vaccination along with IL-2 or GM-CSF. Proc Am Soc Clin Oncol 19: 463a(abstract#1818), 2000Google Scholar
  83. 83.
    Bouvet M, Bold RJ, Lee J, Evans DB, Abbruzzese JL, Chiao PJ, McConkey DJ, Chandra J, Chada S, Fang P, Roth JA: Adenovirus-mediated wild-type p53 tumor suppressor gene therapy induces apoptosis and suppresses growth of human pancreatic cancer [see comments]. Ann Surg Oncol 5(8): 681–688, 1998Google Scholar
  84. 84.
    Mulvihill SJ, Warren RS, Fell S, Heise C, Maack C, Bergsland E, Venook A, Kirn D: A phase trial of intratumoral injection with an E1B-attenuated adenovirus ONYX-015, into unresectable carcinomas of the exocrine pancreas. Proc Am Soc Clin Oncol 17: 211a(abstract#815), 1998Google Scholar
  85. 85.
    Wilentz RE, Geradts J, Maynard R, Offerhaus GJ, Kang M, Goggins M, Yeo CJ, Kern SE, Hruban RH: Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression. Cancer Res 58(20): 4740–4744, 1998Google Scholar
  86. 86.
    Moskaluk CA, Hruban RH, Kern SE: p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res 57(11): 2140–2143, 1997Google Scholar
  87. 87.
    Goldstein AM, Fraser MC, Struewing JP, Hussussian CJ, Ranade K, Zametkin DP, Fontaine LS, Organic SM, Dracopoli NC, Clark WH Jr, et al.: Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med 333(15): 970–974, 1995Google Scholar
  88. 88.
    Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE: DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271(5247): 350–353, 1996Google Scholar
  89. 89.
    Ghimenti C, Tannergard P, Wahlberg S, Liu T, Giulianotti PG, Mosca F, Fornaciari G, Bevilacqua G, Lindblom A, Caligo MA: Microsatellite instability and mismatch repair gene inactivation in sporadic pancreatic and colon tumours. Br J Cancer 80(1–2): 11–16, 1999Google Scholar
  90. 90.
    Goggins M, Offerhaus GJ, Hilgers W, Griffin CA, Shekher M, Tang D, Sohn TA, Yeo CJ, Kern SE, Hruban RH: Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology. Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. Am J Pathol 152(6): 1501–1507, 1998Google Scholar
  91. 91.
    Park JG, Park YJ, Wijnen JT, Vasen HF: Gene-environment interaction in hereditary nonpolyposis colorectal cancer with implications for diagnosis and genetic testing. Int J Cancer 82(4): 516–519, 1999Google Scholar
  92. 92.
    Jones JB, Song JJ, Hempen PM, Parmigiani G, Hruban RH, Kern SE: Detection of mitochondrial DNA mutations in pancreatic cancer offers a “mass”-ive advantage over detection of nuclear DNA mutations. Cancer Res 61(4): 1299–1304, 2001Google Scholar
  93. 93.
    Sakorafas GH, Tsiotou AG, Tsiotos GG: Molecular biology of pancreatic cancer; oncogenes, tumour suppressor genes, growth factors, and their receptors from a clinical perspective. Cancer Treat Rev 26(1): 29–52, 2000Google Scholar
  94. 94.
    Yamanaka Y, Friess H, Kobrin MS, Buchler M, Beger HG, Korc M: Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. Anticancer Res 13(3): 565–569, 1993Google Scholar
  95. 95.
    Yamanaka Y, Friess H, Buchler M, Beger HG, Uchida E, Onda M, Kobrin MS, Korc M: Overexpression of acidic and basic fibroblast growth factors in human pancreatic cancer correlates with advanced tumor stage. Cancer Res 53(21): 5289–5296, 1993Google Scholar
  96. 96.
    Lemoine NR, Hughes CM, Barton CM, Poulsom R, Jeffery RE, Kloppel G, Hall PA, Gullick WJ: The epidermal growth factor receptor in human pancreatic cancer. J Pathol 166(1): 7–12, 1992Google Scholar
  97. 97.
    Wolff RA: Novel therapies for pancreatic cancer. Cancer J 7(4): 349–358, 2001Google Scholar
  98. 98.
    Abbruzzese JL, Rosenberg A, Xiong Q, LoBuglio A, Schmidt W, Wolff R, Needle M, Waksal H Phase II study of anti-epidermal growth factor receptor (EGFR) antibody cetuximab (IMC-C225) in combination with gemcitabine in patients with advanced pancreatic cancer. Proc Am Soc Clin Oncol 20: 130a(abstract#518), 2001Google Scholar
  99. 99.
    Rowinsky EK, Hammond L, Siu L, Jerabek P, Rizzo J, Denis L, Nemunatis J, Patnaik A, Eckhardt S, Tolcher A, Takimoto C, Ferrante K, Allen LL, Silberman S, Hidalgo M. Dose-schedule-finding, pharmacokinetic, biologic and functional imaging studies of OSI-774, a selective epidermal growth factor receptor tyrosine kinase inhibitor. Proc Am Soc Clin Oncol 20: 2a(abstract#5), 2001Google Scholar
  100. 100.
    Vincent F, Hagiwara K, Ke Y, Stoner GD, Demetrick DJ, Bennett WP: Mutation analysis of the transforming growth factor beta type II receptor in sporadic human cancers of the pancreas, liver, and breast. Biochem Biophys Res Commun 223(3): 561–564, 1996Google Scholar
  101. 101.
    Kornmann M, Beger HG, Korc M: Role of fibroblast growth factors and their receptors in pancreatic cancer and chronic pancreatitis. Pancreas 17(2): 169–175, 1998Google Scholar
  102. 102.
    Day JD, Digiuseppe JA, Yeo C, Lai-Goldman M, Anderson SM, Goodman SN, Kern SE, Hruban RH: Immunohistochemical evaluation of HER-2/neu expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasms. Hum Pathol 27(2): 119–124, 1996Google Scholar
  103. 103.
    Tomaszewska R, Okon K, Nowak K, Stachura J: HER-2/Neu expression as a progression marker in pancreatic intraepithelial neoplasia. Pol J Pathol 49(2): 83–92, 1998Google Scholar
  104. 104.
    Safran H, Ramanathan R, Schwartz J, King T, Steinhoff M, Nauman C, Hesketh P, Ianitti D, Quirk D, Akerman P, Cioffi W, Rathore R, Moore T, Ramdin N, Mass R, Wolff R: Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress Her-2/neu. Proc Am Soc Clin Oncol 20: 155a(abstract#517), 2001Google Scholar
  105. 105.
    Jayson GC, Mulatero C, Ranson M, Zweit J, Hastings D, Julyan P, Lawrance J, McGown A, Jackson A, Haroon H, Hakannson L, Wagstaff J, Groenewegen G, Lehmann F, Levitt D, Tang T, Zweirzina H: Anti-VEGF antibody HuMV833: an EORTC biological treatment development group phase I toxicity, pharmacokinetic and pharmacodynamic study. Proc Am Soc Clin Oncol 20: 4a(abstract#14), 2001Google Scholar
  106. 106.
    Via LE, Gore-Langton RE, Pluda JM: Clinical trials referral resource. Current clinical trials administering the antiangiogenesis agent SU5416. Oncology (Huntingt) 14(9): 1312, 1315–1316, 1321–1323, 2000Google Scholar
  107. 107.
    Kudelka AP, Levy T, Verschraegen CF, Edwards CL, Piamsomboon S, Termrungruanglert W, Freedman RS, Kaplan AL, Kieback DG, Meyers CA, Jaeckle KA, Loyer E, Steger M, Mante R, Mavligit G, Killian A, Tang RA, Gutterman JU, Kavanagh JJ: A phase I study of TNP-470 administered to patients with advanced squamous cell cancer of the cervix. Clin Cancer Res 3(9): 1501–1505, 1997Google Scholar
  108. 108.
    Herbst RS, Tran HT, Mullani NA, Charnsangavej C, Madden TL, Hess KR, Davis D, McConkey DJ, Baker C, O'Reilly M, Ellis LM, Kim E, Bucana C, Lee AT, Roach JS, Terry KA, Gravel DM, Dourado JE, Pluda JM, Fidler IJ, Hong W, Abbruzzese JL: Phase I clinical trial of recombinant human endostatin in patients with solid tumors pharmacokinetic, safety and efficacy analysis using surrogate endpoints of tissue and radiologic response. Proc Am Soc Clin Oncol 20: 3a(abstract#9), 2001Google Scholar
  109. 109.
    Abbruzzese JL, Levin B, Ajani JA, Faintuch JS, Pazdur R, Saks S, Edwards C, Gutterman JU: A phase II trial of recombinant human interferon-gamma and recombinant tumor necrosis factor in patients with advanced gastrointestinal malignancies: results of a trial terminated by excessive toxicity. J Biol Response Mod 9(5): 522–527, 1990Google Scholar
  110. 110.
    Crowell PL, Chang RR, Ren ZB, Elson CE, Gould MN: Selective inhibition of isoprenylation of 21–26–kDa proteins by the anticarcinogen d-limonene and its metabolites. J Biol Chem 266(26): 17679–17685, 1991Google Scholar
  111. 111.
    Ariazi EA, Satomi Y, Ellis MJ, Haag JD, Shi W, Sattler CA, Gould MN: Activation of the transforming growth factor beta signaling pathway and induction of cytostasis and apoptosis in mammary carcinomas treated with the anticancer agent perillyl alcohol. Cancer Res 59(8): 1917–1928, 1999Google Scholar
  112. 112.
    Jaffee EM, Hruban R, Biedzycki B, Laheru D, Schepers K, Sauter P, Grochow L, O'Reilly S, Abrams R, Lillemoe K, Cameron J, Yeo C. Bioactivity of a human GM-CSF tumor vaccine for the treatment of pancreatic adenocarcinoma. Proc Am Soc Clin Oncol 19: 455a(abstract#1784), 2000Google Scholar
  113. 113.
    Greten TF, Jaffee EM: Cancer vaccines. J Clin Oncol 17(3): 1047–1060, 1999Google Scholar
  114. 114.
    Jaffee EM, Hruban RH, Biedrzycki B, Laheru D, Schepers K, Sauter PR, Goemann M, Coleman J, Grochow L, Donehower RC, Lillemoe KD, O'Reilly S, Abrams RA, Pardoll DM, Cameron JL, Yeo CJ: Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol 19(1): 145–156, 2001Google Scholar
  115. 115.
    Smith JP, Verderame MF, Zagon IS: Antisense oligonucleotides to gastrin inhibit growth of human pancreatic cancer. Cancer Lett 135(1): 107–112, 1999Google Scholar
  116. 116.
    Group GTS. Radiation therapy combined with adriamycin or 5–fluorouracil for the treatment of locally unresectable pancreatic carcinoma. Gastrointestinal Tumor Study Group. Cancer 56(11): 2563–2568, 1985Google Scholar
  117. 117.
    Todd KE, Gloor B, Lane JS, Isacoff WH, Reber HA: Resection of locally advanced pancreatic cancer after downstaging with continuous-infusion 5–fluorouracil, mitomycin-C, leucovorin, and dipyridamole. J Gastrointest Surg 2(2): 159–166, 1998Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Corina E. Akerele
    • 1
  • Irina Rybalova
    • 1
  • Howard L. Kaufman
    • 2
  • Sridhar Mani
    • 1
  1. 1.Albert Einstein Cancer CenterMontefiore Medical CenterBronx
  2. 2.Herbert Irving Cancer CenterColumbia Presbyterian Medical CenterNew YorkUSA

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