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Current Approaches and Future Strategies for Pancreatic Carcinoma

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Abstract

Pancreatic cancer is a lethal disease characterized bylocal invasion and early dissemination. It isresistant to conventional surgical, radiotherapeutic,and chemotherapeutic modalities. These interventionshave had minimal impact on overall survival with veryfew patients enjoying long term survival. Over thepast few years, 2′difluoro-2′deoxycytidine(gemcitabine) has demonstrated modest activity in thisdisease and investigations are proceeding to expandits role in combination with radiotherapy and otherchemotherapeutic agents. In addition, theidentification of the molecular defects underlyingthis disease has suggested molecular targets for thedesign of rational systemic therapy. These targetsinclude matrix metalloproteinases, K-ras, HER2/neu,p53, and the epidermal growth factorreceptor. Current and future clinical trials designedto improve the survival of patients with pancreaticcancer will be discussed.

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References

  1. Landis SH, Murray T, Bolden S, Wingo PA: Cancer Statistics, 1999. CA Cancer J Clin 49: 8-31, 1999

    Google Scholar 

  2. Evans DB, Abbruzzese JL, Rich TR: Cancer of the Pancreas. In: DeVita VT, Hellman S, and Rosenberg SA (eds) Cancer Principles and Practice of Oncology. Fifth Edition. Lippincott-Raven, Philadelphia, 1997, pp 1054-1087

    Google Scholar 

  3. Cubilla AL, Fitzgerald PJ: Morphological lesions associated with human primary invasive nonendocrine pancreas cancer. Cancer Res 36: 2690-2698, 1976

    Google Scholar 

  4. Hruban RH, van Mansfeld AD, Offerhaus GJ, van Weering DH, Allison DC, Goodman SN, Kensler TW, Bose KK, Cameron JL, Bos JL: K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol 143: 545-554, 1993

    Google Scholar 

  5. 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: 4740-4744, 1998

    Google Scholar 

  6. Terhune PG, Phifer DM, Tosteson TD, Longnecker DS: K-ras mutation in focal proliferative lesions of human pancreas. Cancer Epidemiol Biomarkers Prev 7: 515-521, 1998

    Google Scholar 

  7. Casey G, Yamanaka Y, Friess H, Kobrin MS, Lopez ME, Buchler M, Beger HG, Korc M: p53 mutations are common in pancreatic cancer and are absent in chronic pancreatitis. Cancer Lett 69: 151-160, 1993

    Google Scholar 

  8. Howe LR, Leevers SJ, Gomez N, Nakielny S, Cohen P, Marshall CJ: Activation of the MAP kinase pathway by the protein kinase raf. Cell 71: 335-342, 1992

    Google Scholar 

  9. Longnecker DS, Terhune PG: What is the true rate of K-ras mutation in carcinoma of the pancreas? Pancreas 17: 323-324, 1998

    Google Scholar 

  10. Masson P, Andren-Sandberg A: Crude Isolation of DNA from unselected human pancreatic tissue and amplification by the polymerase chain reaction of K-ras oncogene to detect point mutations in pancreatic cancer. Acta Oncol 31: 421-424, 1992

    Google Scholar 

  11. Pellegata NS, Sessa F, Renault B, Bonato M, Leone BE, Solcia E, Ranzani GN: K-ras and p53 gene mutations in pancreatic cancer: ductal and nonductal tumors progress through different genetic lesions. Cancer Res 54: 1556-1560, 1994

    Google Scholar 

  12. Konishi Y, Tsutsumi M, Tsujiuchi T: Mechanistic analysis of pancreatic ductal carcinogenesis in hamsters. Pancreas 16: 300-306, 1998

    Google Scholar 

  13. de Winter JP, Roelen BA, ten Dijke P, van der Burg B, van den Eijnden-van Raaij AJ: DPC4 (SMAD4) mediates transforming growth factor-beta1 (TGF-beta1) induced growth inhibition and transcriptional response in breast tumour cells. Oncogene 14: 1891-1899, 1997

    Google Scholar 

  14. Goldstein AM, Fraser MC, Struewing JP, Hussussian CJ, Ranade K, Zametkin DP, Fontaine LS, Organic SM, Dracopoli NC, Clark WH Jr, Tucker MA: Increased risk of pancreatic cancer in melanoma-prone kindreds with p16(supINK4) mutations. N Engl J Med 333: 970-974, 1995

    Google Scholar 

  15. Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE: Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 8: 27-32, 1994

    Google Scholar 

  16. Korc M: Role of growth factors in pancreatic cancer. Surg Oncol Clin N Am 7: 25-41, 1998

    Google Scholar 

  17. Day JD, DiGiuseppe JA, Yao C, Lai-Goldman MC, Anderson SM, Goodman SN, Kern SE, Hruban RH: Immunohistochemical evaluation of HER2/neu expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasms. Hum Pathol 2: 119-124, 1996

    Google Scholar 

  18. Yamanaka Y, Friess H, Kobrin MS, Buchler M, Kunz J, Beger HG, Korc M: Overexpression of HER2/neu oncogene in human pancreatic carcinoma. Hum Pathol 24: 1127-1134, 1993

    Google Scholar 

  19. Yamanaka Y, Friess H, Korbin MS, Buchler M, Beger HG, Korc M: Coexpression of epidermal growth factor receptor expression and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. Anticancer Res 13: 565-570, 1993

    Google Scholar 

  20. Korc M, Chandrasekar B, Yamanaka Y, Friess H, Buchier M, Beger HG: Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increases in the levels of epidermal growth factor and transforming growth factor alpha. J Clin Invest 90: 1352-1360, 1992

    Google Scholar 

  21. Miller DW, Fontain M, Kolar C, Lawson T: The expression of multidrug resistance-associated protein (MRP) in pancreatic adenocarcinoma cell lines. Cancer Lett 107: 301-306, 1996

    Google Scholar 

  22. Wang CY, Mayo MW, Baldwin AS Jr.: TNF-and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. Science 274: 784-787, 1996

    Google Scholar 

  23. Sonenshein GE: Rel/NF-κB transcription factors and the control of apoptosis. Semin Cancer Biol 8: 113-119, 1997

    Google Scholar 

  24. Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary K, Chiao PJ: Constitutive activation of NF-κB RelA transcription factor involves Ras and MAP kinases in human pancreatic adenocarcinoma cells. (Submitted)

  25. Dimitroff CJ, Sharma A, Bernacki RJ: Cancer metastasis: a search for therapeutic inhibition. Cancer Invest 16: 279-290, 1998

    Google Scholar 

  26. Koshiba T, Hosotani R, Wada M, Miyamoto Y, Fujimoto K, Lee JU, Doi R, Arii S, Imamura M: Involvement of matrix metalloproteinase-2 activity in invasion and metastasis of pancreatic carcinoma. Cancer 82: 642-650, 1998

    Google Scholar 

  27. Bramhall SR, Neoptolemos JP, Stamp GW, Lemoine NR: Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma. J Pathol 182: 347-355, 1997

    Google Scholar 

  28. Denis LJ, Verweij J: Matrix metalloproteinase inhibitors: present achievements and future prospects. Invest New Drugs 15: 175-185, 1997

    Google Scholar 

  29. Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T, Kerbel RS: Mutant ras oncogenes upregulate VEG-F/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 55: 4575-4580, 1995

    Google Scholar 

  30. Chiao P, Wang W, Ellis L, Shen D, Abbruzzese J, Evans D: NF-κB regulates VEG-F gene expression in human pancreatic cancers. Proc Am Assoc Cancer Res 37: 525, 1996 (abstract #3591)

    Google Scholar 

  31. Wang W, Larry L, Evans DB, Abbruzzese JL, Boyd D, Chiao PJ: Overexpression of urokinase-type plasminogen activator in pancreatic adenocarcinoma is regulated by constitutively activated RelA. Proc Am Assoc Cancer Res 39: 48, 1998 (abstract #328)

    Google Scholar 

  32. Karayiannakis AJ, Syrigos KN, Chatzigianni E, Papanikolaou S, Alexiou D, Kalahanis N, Rosenberg T, Bastounis E: Aberrant E-cadherin expression associated with loss of differentiation and advanced stage in human pancreatic cancer. Anticancer Res 18: 4177-4180, 1998

    Google Scholar 

  33. Weinel RJ, Neumann K, Kisker O, Rosendahl A: Expression and potential role of E-cadherin in pancreatic carcinoma. Int J Pancreatol 19: 25-30, 1996

    Google Scholar 

  34. Kuniyasu H, Ellis LM, Evans DB, Abbruzzese JL, Fenoglio CJ, Bucana CD, Cleary KR, Tahara E, Fidler IJ: Relative Expression of E-Cadherin and Type IV Collagenease Genes Predicts Disease Outcome in Patients with Resectable Pancreatic Carcinoma. Clin Cancer Res 5: 25-33, 1999

    Google Scholar 

  35. Hubbard KP, Pazdur R, Ajani JA, Braud E, Blaustein A, King M. Llenado-Lee M, Winn R, Levin B, Abbruzzese JL: Phase II evaluation of iproplatin in patients with advanced gastric and pancreatic cancer. Am J Clin Oncol 15: 524-527, 1992

    Google Scholar 

  36. Carlson RW, Doroshow JH, Odujinrin OO, Flam MS, Malec M, Lamborn KR: Trimetrexate in locally advanced or metastatic adenocarcinoma of the pancreas. A phase II study of the Northern California Oncology Group. Invest New Drugs 8: 387-389, 1990

    Google Scholar 

  37. Casper ES, Schwartz GK, Johnson B, Kelsen DP: Phase II trial of edatrexate in patients with advanced pancreatic adenocarcinoma. Invest New Drugs 10(4): 313-316, 1992

    Google Scholar 

  38. Casper ES, Schwartz GK, Kelsen DP: Phase II trial of fazarabine (arabinofuranosyl-5-azacytidine) in patients with advanced pancreatic adenocarcinoma. Invest New Drugs 10: 205-209, 1992

    Google Scholar 

  39. Bukowski RM, Fleming TR, Macdonald JS, Oishi N, Taylor SA, Baker LH: Evaluation of combination chemotherapy and phase II agents in pancreatic adenocarcinoma. A Southwest Oncology Group study. Cancer 71: 322-325, 1993

    Google Scholar 

  40. Linke K, Pazdur R, Abbruzzese JL, Ajani JA, Winn R, Bradof JE, Daugherty K, Levin B: Phase II study of amonafide in advanced pancreatic adenocarcinoma. Invest New Drugs 9: 353-356, 1991

    Google Scholar 

  41. Rougier PH, De Forni M, Adenis A, Ducreux M, Djazouli K, Adams D, Bonneterre J, Clouet P, Blanc C, Bayssas M, Armand JP: phase II study of Taxotere (RP56976, docetaxel) in pancreatic adenocarcinoma. Proc Am Soc Clin Oncol 13: 200, 1994 (abstract #587)

    Google Scholar 

  42. Okada S, Sakata Y, Matsuno S, Kurihara M, Sasaki Y, Ohashi Y, Taguchi T: Phase II study of docetaxel in patients with metastatic pancreatic cancer: a Japanese cooperative study. Cooperative Group of Docetaxel for Pancreatic Cancer in Japan. Br J Cancer 80: 438-443, 1999

    Google Scholar 

  43. Sugarman SM, Pazdur R, Daugherty K, Evans D, Winn R, Dubovsky D, Goodwin JW, Abbruzzese JL: A phase II trial of topotecan for the treatment of unresectable pancreatic cancer. Proc Am Soc Clin Oncol 14: 224a, 1994 (abstract #684)

    Google Scholar 

  44. Wagener DJ, Verdonk HE, Dirix LY, Catimel G, Siegenthaler P, Buitenhuis M, Mathieu-Boue A, Verweij J: phase II trial of CPT-11 in patients with advanced pancreatic cancer, An EORTC Early Clinical Trials Group study. Ann Oncol 6: 129-132, 1995

    Google Scholar 

  45. 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: 29-34, 1994

    Google Scholar 

  46. Rubin J, Gallagher JG, Schroeder G, Schutt AJ, Dalton RJ, Kugler JW, Morton RF, Mailliard JA, Burch PA: Phase II trials of 5-fluorouracil and leucovorin in patients with metastatic gastric or pancreatic carcinoma. Cancer 78: 1888-1891, 1996

    Google Scholar 

  47. Pazdur R, Meropol NJ, Casper ES, Fuchs C, Douglass HO Jr, Vincent M, Abbruzzese JL: phase II trial of ZD1694 (TOMUDEX) in patients with advanced pancreatic cancer. Invest New Drugs 13: 355-358, 1996

    Google Scholar 

  48. Kelsen D: The use of chemotherapy in the treatment of advanced gastric and pancreas cancer. Semin Oncol 21: 58-66, 1994

    Google Scholar 

  49. Bukowski RM: Role of chemotherapy in patients with adenocarcinoma of the pancreas. Adv Oncol 11: 25-29, 1995

    Google Scholar 

  50. Carter SK, Comis RL: The integration of chemotherapy into a combined modality approach for cancer treatment. VI. Pancreatic adenocarcinoma. Cancer Treat Rev 2: 193-214, 1975

    Google Scholar 

  51. Ajani JA, Abbruzzese JL, Goudeau P, Faintuch J, Yeomans A, Boman B, Levin B: Ifosfamide and mesna: Marginally active in patients with cancer of the pancreas. J Clin Oncol 6: 1703-1707, 1988.

    Google Scholar 

  52. Bissery MC, Guenard D, Gueritte-Voegelein F, Lavelle F: Experimental antitumor activity of Taxotere (RP 56976, NSC 628503), a Taxol analogue. Cancer Res 51: 4845-4852, 1991

    Google Scholar 

  53. Abbruzzese JL, Evans D, Gravel D, Markowitz A, Patt Y, Pazdur R: Docetaxel, a potentially active agent for patients with pancreatic adenocarcinomas. Proc Am Soc Clin Oncol 14: 221, 1995 (abstract #561)

    Google Scholar 

  54. Hertel LW, Kroin JS, Misner JW, Tustin JM: Synthesis of 2-deoxy-2′,2′difluro-D-ribose and 2-deoxy-2′,2′difluro-D-fibofuranosyl nucleosides. J Org Chem 53: 2406-2409, 1988

    Google Scholar 

  55. Hertel LW, Boder GB, Kroin JS, Rinzel SM, Poore GA, Todd GC, Grindey: Evaluation of the antitumor activity of gemcitabine (2′,2′-difluoro-2′-deoxycytidine). Cancer Res 50: 4417-4422, 1990

    Google Scholar 

  56. Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, Nowak B, Mineishi S, Tarassoff P, Satterlee W, Raber MN, Plunkett W: A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9: 491-498, 1991

    Google Scholar 

  57. Burris HA 3rd, 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: 2403-2413, 1997

    Google Scholar 

  58. Rothenberg ML, Moore MJ, Cripps MC, Andersen JS, Portenoy RK, Burris HA III, 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: 347-353, 1996

    Google Scholar 

  59. Brand R, Capadano M, Tempero M: A phase I trial of weekly gemcitabine administered as a prolonged infusion in patients with pancreatic cancer and other solid tumors. Invest New Drugs 15: 331-341, 1997

    Google Scholar 

  60. Touroutoglou N, Gravel D, Raber MN, Plunkett W, Abbruzzese JL: Clinical results of a pharmacodynamicallybased strategy for higher dosing of gemcitabine in patients with solid tumors. Ann Oncol 9: 213-216, 1998

    Google Scholar 

  61. Fossella FV, Lippman SM, Shin DM, Tarassoff P, Calayag-Jung M, Perez-Soler R, Lee JS, Murphy WK, Glisson B, Rivera E, Hong WK: Maximum-tolerated dose defined for single-agent gemcitabine: a phase I dose-escalation study in chemotherapy-naive patients with advanced non-small-cell lung cancer. J Clin Oncol 15: 310-316, 1997

    Google Scholar 

  62. Package Insert for Gemzar (GemcitabineHCl) Issued May 16, 1996.

  63. Tempero M, Plunkett W, Ruiz van Haperen V, Hainsworth J, Hochster H, Lenzi R, Abbruzzese J: Randomized phase II trial of dose intense gemcitabine by standard infusion vs. fixed dose rate inmetastatic pancreatic adenocarcinoma. Proc Am Soc Clin Oncol 18: 273a, 1997 (abstract #1048)

    Google Scholar 

  64. Shewach DS, Hahn TM, Chang E, Hertel LW, Lawrence TS: Metabolism of 2′,2′-difluoro-2′-deoxycytidine and radiation sensitization of human colon carcinoma cells. Cancer Res 54: 3218-3223, 1994

    Google Scholar 

  65. Lawrence TS, Chang EY, Hahn TM, Hertel LW. Shewach DS: Radiosensitization of Pancreatic Cancer Cells by 2′,2′-Difluoro-2′-Deoxycytidine. Int J Rad Oncol Biol Phys 34: 867-872, 1996

    Google Scholar 

  66. Eisbruch A, Shewach DS, Urba S, Wolf GT, Bradford CR, Marentette LJ, Terrell JE, Hogikyan ND, Esclamado RM, Lawrence TS: phase I trial of radiation concurrent with low dose gemcitabine for head and neck cancer: high mucosal and pharyngeal toxicity. Proc Am Soc Clin Oncol 16: 386a, 1997 (abstract #1377)

    Google Scholar 

  67. Goor C, Scalliet P, Van Meerbeek J, Galdermans D, Groen HJM, Van der Leest AHD, Westerink H, Poelman M: A phase II study combining gemcitabine with radiotherapy in stage III NSCLC Ann Oncol 7: 101, (Suppl 5) 1996, (abstract #481)

    Google Scholar 

  68. Wolff RA, Evans DB, Gravel DM, Lenzi R, Pisters PW, Lee JE, Janjan NA, Goswitz MS, Abbruzzese JL: phase I Trial of Gemcitabine (GEM) Combined with Radiation (XRT) for the Treatment of Locally Advanced Pancreatic Adenocarcinoma. Proc Am Soc Clin Oncol 17: 283a, 1998 (abstract #1091)

    Google Scholar 

  69. McGinn CJ, Smith DC, Szarka CE, Pinover WH, Loehrer PJ, Morphis JG, Nicol S, Shewach DS, Lawrence TS, O'Dwyer PJ: A phase I Study of Gemcitabine (GEM) in Combination with Radiation Therapy (RT) in Patients with Localized, Unresectable Pancreatic Cancer. Proc Am Soc Clin Oncol 17: 264a, 1998 (abstract #1014)

    Google Scholar 

  70. Blackstock AW, Bernard SA, Richards F, Savage P, Tepper JE: phase I Study of Concurrent Radiation and Twice-Weekly Gemcitabine in Advanced/Metastatic Pancreatic Cancer. Proc Am Soc Clin Oncol 17: 264a, 1998 (abstract #1015)

    Google Scholar 

  71. 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 Surgery 171: 118-125, 1996

    Google Scholar 

  72. Radiation Therapy Oncology Group Study, RTOG-97-04: A phase III Study of Pre and Post Chemoradiation 5-FU vs. Pre and Post Chemoradiation Gemcitabine for Postoperative Adjuvant Treatment of Resected Pancreatic Adenocarcinoma

  73. Colucci G, Giuliani F, Lopez M, Gebbia V, Pedicini A, Biglietto M, Cartení G, Maiello E, Gebbia N: Gemcitabine alone or with cisplatin in advanced pancreatic cancer: Preliminary results of a randomized study of the Southern Italy Oncology Group. Proc Am Soc Clin Oncol 17: 288a, 1998 (abstract #1112)

    Google Scholar 

  74. Hidalgo M, Castellano D, Paz-Ares L, Gravalos C, Diaz-Puente M, Hitt R, Alonso S, Cortes-Funes H: Phase I-II Study of Gemcitabine and Fluorouracil as a Continuous Infusion in Patients With Pancreatic Cancer. J Clin Oncol 17: 585-592, 1999

    Google Scholar 

  75. Eastern Cooperative Oncology Group Study E2297: Phase III randomized study of gemcitabine with or without fluorouracil in patients with advanced pancreatic adenocarcinoma.

  76. Verschraegen CF, Natelson EA, Giovanella BC, Kavanagh JJ, Kudelka AP, Freedman RS, Edwards CL, Ende K, Stehlin JS: A phase I clinical and pharmacological study of oral 9-nitrocamptothecin, a novel water-insoluble topoisomerase I inhibitor. Anticancer Drugs 9: 36-44, 1998

    Google Scholar 

  77. Stehlin JS, Giovanella BC, Natelson EA, De Ipolyi PD, Coil DR, Davis B, Wolk D, Wallace P, Trojacek A: A study of 9-nitrocamptothecin (RFS-2000) in patients with advanced pancreatic. Int J Onc 14: 821-831, 1999.

    Google Scholar 

  78. Mohammad RM, Al-Katib A, Pettit GR, Vaitkevicius VK, Joshi U, Adsay V, Majumdar AP, Sarkar FH: An Orthotopic Model of Human Pancreatic Cancer in Severe Combined Immunodeficient Mice: Potential Application for Preclinical Studies. Clin Cancer Res 4: 887-894, 1998

    Google Scholar 

  79. Pitot HC, McElroy Jr. EA, Reid JM, Windebank AJ, Sloan JA, Erlichman C, Bagniewski PG, Walker DL, Rubin J, Goldberg RM, Adjei AA, Ames MM: phase I trial of dolastatin-10 (NSC 376128) in patients with advanced solid tumors. Clin Cancer Res 5: 525-531, 1999

    Google Scholar 

  80. Tran HT, Newman RA, Beck DE, Huie R, Abbruzzese J, Madden T: A phase I pharmacokinetic/pharmacodynamic study of dolastatin-10 in adult patients with advanced solid tumors. Proc Am Assoc Cancer Res 38: 306, 1997 (abstract #2056)

    Google Scholar 

  81. Gibbs JB, Oliff A, Kohl NE: Farnesyltransferase inhibitors: ras research yields a potential cancer therapeutic. Cell 77: 175-178, 1994

    Google Scholar 

  82. Gibbs JB, Oliff A: Pharmaceutical research in molecular oncology. Cell 79: 193-198, 1994

    Google Scholar 

  83. Sun J, Qian Y, Hamilton AD, Sebti SM: Ras CAAX peptidomimetic FTI 276 selectively blocks tumor growth in nude mice of a human lung carcinoma with K-Ras mutation and p53 deletion. Cancer Res 55: 4243-4247, 1995

    Google Scholar 

  84. Hohl RJ, Lewis K: Differential effects of monoterpenes and lovastatin on RAS processing. J Biol Chem 270: 17508-17512, 1995

    Google Scholar 

  85. Stark MJ, Burke YD, McKinzie JH, Ayoubi AS, Crowell PL: Chemotherapy of pancreatic cancer with the monoterpene perillyl alcohol. Cancer Lett 96: 15-21, 1995

    Google Scholar 

  86. Ripple GH, Gould MN, Stewart JA, Tutsch KD, Arzoomanian RZ, Alberti D, Feierabend C, Pomplun M, Wilding G, Bailey HH: phase I clinical trial of perillyl alcohol administered daily. Clin Cancer Res 4: 1159-1164, 1998

    Google Scholar 

  87. Montoya RG, Velasco MA, Price RE, Abbruzzese JL, Wargovich MJ: Pilot study on the chemoprevention of N-Nitrosobis(2-oxopropyl)amine-induced cancers of the pancreas in Syrian golden hamsters by the monoterpene perillyl alcohol. Proc Am Assoc Cancer Res 37: 274, 1996 (abstract #1872)

    Google Scholar 

  88. Klijn JG, Hoff AM, Planting AS, Verweij J, Kok T, Lamberts SW, Portengen H, Foekens JA: Treatment of patients with metastatic pancreatic and gastrointestinal tumours with the somatostatin analogue Sandostatin: a phase II study including endocrine effects. Br J Cancer 62: 627-630, 1990

    Google Scholar 

  89. Savage AP, Calam J, Wood CB, Bloom SR: SMS 201-995 Treatment and advanced intestinal cancer: a pilot study. Aliment Pharmacol Ther 1: 133-139, 1987

    Google Scholar 

  90. Canobbio L, Boccardo F, Cannata D, Gallotti P, Epis R: Treatment of advanced pancreatic carcinoma with the somatostatin analogue BIM 23014. Preliminary results of a pilot study. Cancer 69: 648-650, 1992

    Google Scholar 

  91. Pederzoli P, Maurer U, Vollmer K, Buechler M, Kjaeve J, Van Cutsem E, Di Carlo V, Stauder H, Bergan A, Ebert M, Kiese B, Raymond MC, Kay A: phase 3 Trial of SMS 201-995 pa LAR (SMS pa LAR) vs. Placebo in Unresectable Stage II, III, and IV Pancreatic Cancer. Proc Am Soc Clin Oncol 17: 257a, 1998 (abstract #988)

    Google Scholar 

  92. Roy A, Jacobs A, Bukowski R, Cunningham D, Hamm J, Schlag PM, Rosen P, Francois E, Finley G, Lipton A, Bruckner H, Haller D, Conroy T, Goel R, Price P, Smith G, Mietlowski W, Linnartz R, Russo D, Kay A: phase 3 Trial of SMS 201-995 pa LAR (SMS PA LAR) and Continuous Infusion (CI) 5-FU in Unresectable Stage II, III, and IV Pancreatic Cancer. Proc Am Soc Clin Oncol 17: 257a, 1998 (abstract #987)

    Google Scholar 

  93. Radulovic S, Nagy A, Szoke B, Schally AV: Cytotoxic analog of somatostatin containing methotrexate inhibits growth of MIA PaCa-2 human pancreatic cancer xenografts in nude mice. Cancer Lett 62: 263-271, 1992

    Google Scholar 

  94. Smith-Jones PM, Stolz B, Albert R, Ruser G, Briner U, Macke HR, Bruns C: Synthesis and characterisation of [90Y]-Bz-DTPA-oct: a ytrium-90-labelled octreotide analogue for radiotherapy of somatostatin receptor-positive tumours. Nucl Med Biol 25: 181-188, 1998

    Google Scholar 

  95. Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, School S, Fehrenbacher L, Paton V, Shak S, Lieberman G, Slamon D. Efficacy and safety of Herceptin (humanized anti-HER2 antibody) as a single agent in 222 women with HER2 overexpression who relapsed following chemotherapy for metastatic breast cancer. Proc Am Soc Clin Oncol 17: 97a, 1998 (abstract #376)

    Google Scholar 

  96. Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, Sklarin NT, Seidman AD, Hudis CA, Moore J, Rosen PP, Twaddell T, Henderson IC, Norton L: phase II study of weekly intravenous recombinant humanized antip185HER2 monoclonal antibody in patients with HER2/neuoverexpressing metastatic breast cancer J Clin Oncol 14: 737-744, 1996

    Google Scholar 

  97. Baselga J, Norton L, Albanell J, Kim YM, Mendelsohn J: Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res 58: 2825-2831, 1998

    Google Scholar 

  98. Norton L, Slamon D, Leyland-Jones B, Wolter J, Fleming T, Eirmann W, Baselga J, Mendelsohn J, Bajamonde A, Ash M, and Shak, S for the Multinational Herceptin Investigator Group: Overall survival advantage to simultaneous chemotherapy plus the humanized anti-HER2 monoclonal antibody Herceptin in HER2-overexpressing metastatic breast cancer. Proc Am Soc Clin Oncol 18: 127a, 1998 (abstract #483)

    Google Scholar 

  99. Mendelsohn J: Epidermal growth factor receptor inhibition by a monoclonal antibody as anticancer therapy. Clin Cancer Res 3: 2703-2707, 1997

    Google Scholar 

  100. Bruns CJ, Portera CA, Tsan R, Hicklin DJ, Radinsky R: Regression of human pancreatic carcinoma growing orthotopically in athymic nude mide by blockade of epidermal growth factor receptor (EGF-R) signaling in combination with Gemcitabine. Proc Am Assoc for Cancer Res 40: 23, 1999 (abstract #154)

    Google Scholar 

  101. Bramhall SR: The matrix metalloproteinases and their inhibitors in pancreatic cancer. From molecular science to a clinical application. Int J Pancreatol 21: 1-12, 1997

    Google Scholar 

  102. Rasmussen H, Rugg T, Brown P, Baillet M, Millar A: A 371 patient meta-analysis of studies of marimastat in patients with advanced cancer. Proc Am Soc Clin Oncol 16: 429a, 1997 (abstract #1538)

    Google Scholar 

  103. Fong TA. Shawver LK. Sun L. Tang C. App H. Powell TJ. Kim YH. Schreck R. Wang X. Risau W. Ullrich A. Hirth KP. McMahon G. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res 59: 99-106, 1999

    Google Scholar 

  104. Figg WD. Pluda JM. Lush RM. Saville MW. Wyvill K. Reed E. Yarchoan R. The pharmacokinetics of TNP-470, a new angiogenesis inhibitor. Pharmacotherapy 17: 91-97, 1997

    Google Scholar 

  105. 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: 1501-1505, 1997

    Google Scholar 

  106. O'Reilly MS. The preclinical evaluation of angiogenesis inhibitors. Invest New Drugs 15: 5-13, 1997

    Google Scholar 

  107. O'Reilly MS. Holmgren L. Chen C. Folkman J. Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 2: 689-692, 1996

    Google Scholar 

  108. Cao Y. O'Reilly MS. Marshall B. Flynn E. Ji RW. Folkman J. Expression of angiostatin cDNA in a murine fibrosarcoma suppresses primary tumor growth and produces long-term dormancy of metastases. J Clin Invest 101: 1055-1063, 1998

    Google Scholar 

  109. Bouvet M, Bold RJ, Lee J, Evans DB, Abbruzzese JL, Chiao PJ, McConkey DJ, Chandra J, Chada S, Fang B, Roth JA: Adenovirus-mediated wild-type p53 tumor suppressor gene therapy induces apoptosis and suppresses growth of human pancreatic cancer. Ann Surg Oncol 5: 681-688, 1998

    Google Scholar 

  110. Joshi US, Dergham ST, Chen YQ, Dugan MC, Crissman JD, Vaitkevicius VK, Sarkar FH: Inhibition of pancreatic tumor cell growth in culture by p21WAF1 recombinant adenovirus. Pancreas 16: 107-113, 1998

    Google Scholar 

  111. Hwang RF, Gordon EM, Anderson WF, Parekh D: Gene therapy for primary and metastatic pancreatic cancer with intraperitoneal retroviral vector bearing the wild-type p53 gene. Surgery 124: 143-150, discussion 150-1, 1998

    Google Scholar 

  112. Mukhopadhyay T, Tainsky M, Cavender AC, Roth JA: Specific inhibition of K-ras expression and tumorigenicity of lung cancer cells by antisense RNA. Cancer Res 51: 1744-1748, 1991

    Google Scholar 

  113. Feng M, Cabrera G, Deshane J, Scanlon KJ, Curiel DT: Neoplastic reversion accomplished by high efficiency adenoviralmediated delivery of an anti-ras ribozyme. Cancer Res 55: 2024-2028, 1995

    Google Scholar 

  114. Mulvihill SJ, Warren RS, Fell S, Heise C, Maack C, Bergsland E, Venook A, Kirn D: A phase I 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, 1998 (abstract #815)

    Google Scholar 

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Wolff, R.A., Chiao, P., Lenzi, R. et al. Current Approaches and Future Strategies for Pancreatic Carcinoma. Invest New Drugs 18, 43–56 (2000). https://doi.org/10.1023/A:1006383831045

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