Gentherapeutische Ansätze bei gastrointestinalen Tumoren

Zusammenfassung

Gentherapie ist eine elegante und grundsätzlich nebenwirkungsarme Alternative zu herkömmlichen Therapiestrategien bei Malignomen. Nach dem Enthusiasmus der 90er-Jahre ist Ernüchterung eingekehrt. Im Rahmen dieser Arbeit werden die Werkzeuge und Stellschrauben der Gentherapie (Vektoren, Promotoren, Targeting, therapeutische Gene) sowie die Wirkprinzipien (Enzym-Prodrug-Therapie; genetische Impfung) erklärt. Die klinischen Protokolle und die wenigen abgeschlossenen klinischen Studien zu gastrointestinalen Tumoren werden kritisch reflektiert und ein Ausblick auf die weitere Entwicklung - auch jenseits der klassischen Gentherapie - gegeben.

Abstract

Gene therapy offers an elegant alternative to toxic chemotherapy regimens, mostly without severe side effects. Gene therapy for cancer was one of the first applications. Following the enthusiasm in the early 1990 s, a more rationale view is preferred today. This general review looks at the tools of gene therapy and their principle elements (vector, promoter, targeting, therapeutic genes). The principles of gene therapy such as gene-directed enzyme prodrug therapy (GDEPT) and gene-directed tumor vaccination are explained. Furthermore, published protocols and clinical studies in gastrointestinal oncology are reviewed. Finally, an outlook is given on the latest developments, some of them going beyond the realm of conventional gene therapy.

Gentherapie - Lebermetastasen - Pankreaskarzinom

Gastroenteropancreatic tumors - gene therapy - pancreatic carcinoma - liver metastases

Literatur

• 1 Chong G, Cunningham D. Gastrointestinal cancer: recent developments in medical oncology.  Eur J Surg Oncol. 2005;  31 (5) 453-460
• 2 Culver K W. Gene therapy. A handbook for physicians. New York, NY; Mary Ann Liebert, Inc 1994
• 3 McCormick F. Cancer gene therapy: fringe or cutting edge?.  Nat Rev Cancer. 2001;  1 (2) 130-141
• 4 Raper S E, Chirmule N, Lee F S. et al . Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer.  Mol Genet Metab. 2003;  80 (1 - 2) 148-158
• 5 Mayer-Kuckuk P, Banerjee D, Kemeny N. et al . Molecular therapies for colorectal cancer metastatic to the liver.  Mol Ther. 2002;  5 (5 Pt 1) 492-500
• 6 Thorne S H, Bartlett D L, Kirn D H. The use of oncolytic vaccinia viruses in the treatment of cancer: a new role for an old ally?.  Curr Gene Ther. 2005;  5 (4) 429-443
• 7 Kasuya H, Takeda S, Nomoto S. et al . The potential of oncolytic virus therapy for pancreatic cancer.  Cancer Gene Ther. 2005;  12 (9) 725-736
• 8 Seth P. Vector-Mediated Cancer Gene Therapy: An Overview.  Cancer Biol Ther. 2005;  4 (5) 512-517
• 9 Saukkonen K, Hemminki A. Tissue-specific promoters for cancer gene therapy.  Expert Opin Biol Ther. 2004;  4 (5) 683-696
• 10 Hendrie P C, Russell D W. Gene targeting with viral vectors.  Mol Ther. 2005;  12 (1) 9-17
• 11 Zanetti M, Castiglioni P, Rizzi M. et al . B lymphocytes as antigen-presenting cell-based genetic vaccines.  Immunol Rev. 2004;  199 264-278
• 12 Kanerva A, Hemminki A. Adenoviruses for treatment of cancer.  Ann Med. 2005;  37 (1) 33-43
• 13 Pan X, Li Z S, Xu G M. et al . Adenovirus-mediated gene transfer in the treatment of pancreatic cancer.  Pancreas. 2003;  26 (3) 274-278
• 14 Dachs G U, Tupper J, Tozer G M. From bench to bedside for gene-directed enzyme prodrug therapy of cancer.  Anticancer Drugs. 2005;  16 (4) 349-359
• 15 Fillat C, Carrio M, Cascante A. et al . Suicide gene therapy mediated by the Herpes Simplex virus thymidine kinase gene/Ganciclovir system: fifteen years of application.  Curr Gene Ther. 2003;  3 (1) 13-26
• 16 Brown N L, Lemoine N R. Clinical trials with GDEPT: cytosine deaminase and 5-fluorocytosine.  Methods Mol Med. 2004;  90 451-457
• 17 Mosolits S, Ullenhag G, Mellstedt H. Therapeutic vaccination in patients with gastrointestinal malignancies. A review of immunological and clinical results.  Ann Oncol. 2005;  16 (6) 847-862
• 18 Gleave M E, Monia B P. Antisense therapy for cancer.  Nat Rev Cancer. 2005;  5 (6) 468-479
• 19 Cunningham C, Nemunaitis J. A phase I trial of genetically modified Salmonella typhimurium expressing cytosine deaminase (TAPET-CD, VNP20029) administered by intratumoral injection in combination with 5-fluorocytosine for patients with advanced or metastatic cancer. Protocol no: CL-017. Version: April 9, 2001.  Hum Gene Ther. 2001;  12 (12) 1594-1596
• 20 Glover D J, Lipps H J, Jans D A. Towards safe, non-viral therapeutic gene expression in humans.  Nat Rev Genet. 2005;  6 (4) 299-310
• 21 Scharfmann R, Axelrod J H, Verma I M. Long-term in vivo expression of retrovirus-mediated gene transfer in mouse fibroblast implants.  Proc Natl Acad Sci U S A. 1991;  88 (11) 4626-4630
• 22 Brooks A R, Harkins R N, Wang P. et al . Transcriptional silencing is associated with extensive methylation of the CMV promoter following adenoviral gene delivery to muscle.  J Gene Med. 2004;  6 (4) 395-404
• 23 White J H. Modified steroid receptors and steroid-inducible promoters as genetic switches for gene therapy.  Adv Pharmacol. 1997;  40 339-367
• 24 Walther W, Stein U. Cell type specific and inducible promoters for vectors in gene therapy as an approach for cell targeting.  J Mol Med. 1996;  74 (7) 379-392
• 25 Rossi F M, Guicherit O M, Spicher A. et al . Tetracycline-regulatable factors with distinct dimerization domains allow reversible growth inhibition by p16.  Nat Genet. 1998;  20 (4) 389-393
• 26 Rossi F M, Blau H M. Recent advances in inducible gene expression systems.  Curr Opin Biotechnol. 1998;  9 (5) 451-456
• 27 Lopez C A, Park J O, Mauceri H J. et al . Control of gene therapy by MDR1 and EGR1 promoter sequences in transcriptional targeting by chemotherapy (Review).  Int J Oncol. 2004;  24 (3) 731-736
• 28 Löhr M, Bago Z T, Bergmeister H. et al . Cell therapy using microencapsulated 293 cells transfected a gene construct expressing CYP2B1, an ifosfamide converting enzyme, instilled intra-arterially in patients with advanced-stage pancreatic carcinoma. A phase I-study.  J Mol Med. 1999;  77 393-398
• 29 Tseng J F, Mulligan R C. Gene therapy for pancreatic cancer.  Surg Oncol Clin N Am. 2002;  11 (3) 537-569
• 30 Ruan D T, Warren R S. Liver-directed therapies in colorectal cancer.  Semin Oncol. 2005;  32 (1) 85-94
• 31 Kasuya H, Takeda S, Nomoto S. et al . The potential of oncolytic virus therapy for pancreatic cancer.  Cancer Gene Ther. 2005;  12 (9) 725-736
• 32 Mulvihill S, Warren R, Venook A. et al . Safety and feasibility of injection with an E1B-55 kDa gene-deleted, replication-selective adenovirus (ONYX-015) into primary carcinomas of the pancreas: a phase I trial.  Gene Ther. 2001;  8 (4) 308-315
• 33 Habib N, Salama H, Abd E l Latif Abu Median A. et al . Clinical trial of E1B-deleted adenovirus (dl1520) gene therapy for hepatocellular carcinoma.  Cancer Gene Ther. 2002;  9 (3) 254-259
• 34 Reid T, Galanis E, Abbruzzese J. et al . Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: a phase I trial.  Gene Ther. 2001;  8 (21) 1618-1626
• 35 Bitzer M, Lauer U M. [Oncolytic viruses for genetic therapy of gastrointestinal tumors].  Z Gastroenterol. 2003;  41 (7) 667-674
• 36 Reid T R, Freeman S, Post L. et al . Effects of Onyx-015 among metastatic colorectal cancer patients that have failed prior treatment with 5-FU/leucovorin.  Cancer Gene Ther. 2005;  12 (8) 673-681
• 37 Holm P S, Lage H, Bergmann S. et al . Multidrug-resistant cancer cells facilitate E1-independent adenoviral replication: impact for cancer gene therapy.  Cancer Res. 2004;  64 (1) 322-328
• 38 Sung M W, Yeh H C, Thung S N. et al . Intratumoral adenovirus-mediated suicide gene transfer for hepatic metastases from colorectal adenocarcinoma: results of a phase I clinical trial.  Mol Ther. 2001;  4 (3) 182-191
• 39 Crystal R G, Hirschowitz E, Lieberman M. et al . Phase I study of direct administration of a replication deficient adenovirus vector containing the E. coli cytosine deaminase gene to metastatic colon carcinoma of the liver in association with the oral administration of the pro-drug 5-fluorocytosine.  Hum Gene Ther. 1997;  8 (8) 985-1001
• 40 Habib N A, Sarraf C E, Mitry R R. et al . E1B-deleted adenovirus (dl1520) gene therapy for patients with primary and secondary liver tumors.  Hum Gene Ther. 2001;  12 (3) 219-226
• 41 Ben-Gary H, McKinney R L, Rosengart T. et al . Systemic interleukin-6 responses following administration of adenovirus gene transfer vectors to humans by different routes.  Mol Ther. 2002;  6 (2) 287-297
• 42 Sangro B, Mazzolini G, Ruiz J. et al . Phase I trial of intratumoral injection of an adenovirus encoding interleukin-12 for advanced digestive tumors.  J Clin Oncol. 2004;  22 (8) 1389-1397
• 43 Gilly F N, Sayag-Beaujard A C, Bienvenu J. et al . Gene therapy with AdV-IL2 (TG 1021) in unresectable digestive adenocarcinoma. Phase I-II study, first inclusions.  Adv Exp Med Biol. 1998;  451 527-530
• 44 Gilly F N, Beaujard A, Bienvenu J. et al . Gene therapy with Adv-IL-2 in unresectable digestive cancer: phase I-II study, intermediate report.  Hepatogastroenterology. 1999;  46 Suppl 1 1268-1273
• 45 Sobol R E, Shawler D L, Carson C. et al . Interleukin 2 gene therapy of colorectal carcinoma with autologous irradiated tumor cells and genetically engineered fibroblasts: a Phase I study.  Clin Cancer Res. 1999;  5 (9) 2359-2365
• 46 Habib N A, Hodgson H J, Lemoine N. et al . A phase I/II study of hepatic artery infusion with wtp53-CMV-Ad in metastatic malignant liver tumours.  Hum Gene Ther. 1999;  10 (12) 2019-2034
• 47 Havlik R, Jiao L R, Nicholls J. et al . Gene therapy for liver metastases.  Semin Oncol. 2002;  29 (2) 202-208
• 48 Shimada H, Matsubara H, Ochiai T. p53 gene therapy for esophageal cancer.  J Gastroenterol. 2002;  37 Suppl 14 87-91
• 49 Oohira G, Yamada S, Ochiai T. et al . Growth suppression of esophageal squamous cell carcinoma induced by heavy carbon-ion beams combined with p53 gene transfer.  Int J Oncol. 2004;  25 (3) 563-569
• 50 Morse M. Technology evaluation: Rexin-G, Epeius Biotechnologies.  Curr Opin Mol Ther. 2005;  7 (2) 164-169
• 51 Gordon E M, Cornelio G H, Lorenzo C C. et al . First clinical experience using a ‘pathotropic’ injectable retroviral vector (Rexin-G) as intervention for stage IV pancreatic cancer.  Int J Oncol. 2004;  24 (1) 177-185
• 52 Geissler M, Mohr L, Ali M Y. et al . Immunobiology and gene-based immunotherapy of hepatocellular carcinoma.  Z Gastroenterol. 2003;  41 (11) 1101-1110
• 53 Schmidt-Wolf I G, Finke S, Trojaneck B. et al . Phase I clinical study applying autologous immunological effector cells transfected with the interleukin-2 gene in patients with metastatic renal cancer, colorectal cancer and lymphoma.  Br J Cancer. 1999;  81 (6) 1009-1016
• 54 Rochlitz C, Jantscheff P, Bongartz G. et al . Gene therapy study of cytokine-transfected xenogeneic cells (Vero-interleukin-2) in patients with metastatic solid tumors.  Cancer Gene Ther. 1999;  6 (3) 271-281
• 55 Jaffee E M, Hruban R H, Biedrzycki B. et al . 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. 2001;  19 (1) 145-156
• 56 Palmer D H, Mautner V, Mirza D. et al . Virus-directed enzyme prodrug therapy: intratumoral administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer.  J Clin Oncol. 2004;  22 (9) 1546-1552
• 57 Löhr M, Hoffmeyer A, Kröger J C. et al . Microencapsulated, cellmediated treatment of inoperable pancreatic carcinoma.  Lancet. 2001;  357 1591-1592
• 58 Löhr M, Hoffmeyer A, Kröger J C. et al . Safety, feasibility and clinical benefit of localized chemotherapy using microencapsulated cells for inoperable pancreatic carcinoma: a phase I/II trial.  Cancer Therapy. 2003;  1 121-131
• 59 Winiarczyk S, Gradski Z, Kosztolich B. et al . A clinical protocol for treatment of canine mammary tumors using encapsulated, cytochrome P450 synthesizing cells activating cyclophosphamide: a phase I/II study.  J Mol Med. 2002;  80 (9) 610-614
• 60 Jounaidi Y. Cytochrome P450-based gene therapy for cancer treatment: from concept to the clinic.  Curr Drug Metab. 2002;  3 (6) 609-622
• 61 Samel S, Keese M, Lux A. et al . Peritoneal cancer treatment with CYP2B1 transfected, microencapsulated cells and ifosfamide.  Cancer Gene Ther. 2006;  13 (1) 65-73
• 62 Pearson A S, Bouvet M, Evans D B. et al . Gene therapy and pancreatic cancer.  Front Bioscience. 1998;  3 e230-e237
• 63 Piersanti S, Martina Y, Cherubini G. et al . Use of DNA microarrays to monitor host response to virus and virus-derived gene therapy vectors.  Am J Pharmacogenomics. 2004;  4 (6) 345-356
• 64 Bartholomeusz C, Itamochi H, Yuan L X. et al . Bcl-2 antisense oligonucleotide overcomes resistance to E1A gene therapy in a low HER2-expressing ovarian cancer xenograft model.  Cancer Res. 2005;  65 (18) 8406-8413
• 65 Baggetto L G, Gambrelle J, Dayan G. et al . Major cytogenetic aberrations and typical multidrug resistance phenotype of uveal melanoma: current views and new therapeutic prospects.  Cancer Treat Rev. 2005;  31 (5) 361-379
• 66 Brandt R, Grutzmann R, Bauer A. et al . DNA microarray analysis of pancreatic malignancies.  Pancreatology. 2004;  4 (6) 587-597
• 67 Chen R, Yi E C, Donohoe S. et al . Pancreatic cancer proteome: the proteins that underlie invasion, metastasis, and immunologic escape.  Gastroenterology. 2005;  129 (4) 1187-1197
• 68 Krause D S, Van Etten R A. Tyrosine kinases as targets for cancer therapy.  N Engl J Med. 2005;  353 (2) 172-187
• 69 Jing N, Tweardy D J. Targeting Stat3 in cancer therapy.  Anticancer Drugs. 2005;  16 (6) 601-607
• 70 Izquierdo M. Short interfering RNAs as a tool for cancer gene therapy.  Cancer Gene Ther. 2005;  12 (3) 217-227
• 71 Pascolo S. Messenger RNA-based vaccines.  Expert Opin Biol Ther. 2004;  4 (8) 1285-1294
• 72 Lo H W, Day C P, Hung M C. Cancer-specific gene therapy.  Adv Genet. 2005;  54 235-255
• 73 De Laporte L, Cruz R ea J, Shea L D. Design of modular non-viral gene therapy vectors.  Biomaterials. 2006;  27 (7) 947-954
• 74 Veronese M L, O’Dwyer P J. Monoclonal antibodies in the treatment of colorectal cancer.  Eur J Cancer. 2004;  40 (9) 1292-1301
• 75 Harris M. Monoclonal antibodies as therapeutic agents for cancer.  Lancet Oncol. 2004;  5 (5) 292-302
• 76 Stern M, Herrmann R. Overview of monoclonal antibodies in cancer therapy: present and promise.  Crit Rev Oncol Hematol. 2005;  54 (1) 11-29
• 77 Gilly F N, Beaujard A, Bienvenu J. et al . Gene therapy with Adv-Il-2 in unresectable digestive cancer: Phase I-II study, intermediate report.  Hepatogastroenterol. 1999;  46 1268-1273

1 Alle Abkürzungen finden sich im Glossar am Ende des Artikels