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Geburtshilfe Frauenheilkd 2008; 68(2): 181-186
DOI: 10.1055/s-2008-1038317
Translationale Forschung

© Georg Thieme Verlag KG Stuttgart · New York

Gentherapie gynäkologischer Malignome - ein translationaler Behandlungsansatz

Gene Therapy for Gynaecologic MalignanciesD. T. Rein1 , M. Breidenbach2 , M. Hampl1 , I. Beyer1 , G. J. Bauerschmitz1
  • 1Universitätsfrauenklinik Düsseldorf
  • 2Universitätsfrauenklinik Aachen
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Publication History

Publication Date:
26 February 2008 (online)

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Zusammenfassung

Krebsgentherapie ist vom Grundkonzept her ein vielversprechender neuer Ansatz zur Behandlung von Malignomen, die einer konventionellen Tumortherapie gegenüber resistent sind. Die verschiedenen Ansätze basieren auf den molekularen Unterschieden zwischen normalen Zellen und Tumorzellen, welche für eine gezielte Behandlung genutzt werden. In Bezug auf gynäkologische Malignome wurden in den vergangenen Jahren verschiedene präklinische und klinische Behandlungsansätze entwickelt. Die Daten zeigen eine hohe Therapiesicherheit für die verschiedenen Gentherapieansätze, die klinische Effizienz ist jedoch bis heute unbefriedigend. Eine große Herausforderung liegt somit in der Verbesserung der Effizienz und Spezifität der eingesetzten Gentransfervektoren. Diese Arbeit legt den Schwerpunkt auf aktuelle und zukünftige Gentransferverfahren in der Behandlung gynäkologischer Malignome.

Abstract

Gene therapy is a potentially useful approach for the treatment of malignancies refractory to conventional therapies. Various preclinical and clinical strategies have explored the feasibility of gene therapy for different diseases. Given the urgent need for novel treatment modalities, much of the work to date has focused on gynaecologic malignancies, in particular on ovarian cancer. Although the safety of many approaches has been demonstrated in early phase clinical trials, the efficacy of the different gene therapy approaches has been limited so far. Major challenges include improving gene transfer vectors for enhanced and selective delivery and achieving effective spread of the vector in advanced tumour masses and bulky disease. This review focuses on current and future gene transfer applications for gynaecologic diseases.

Schlüsselwörter

Gentherapie - gynäkologische Tumoren - virale Vektoren

Key words

gene therapy - gynaecologic malignancies - viral vectors

Literatur

  • 1 Kanerva A, Hemminki A. Adenoviruses for treatment of cancer.  Ann Med. 2005;  37 33-43
    PubMedGoogle Scholar
  • 2 Kanerva A, Mikheeva G V, Krasnykh V, Coolidge C J, Lam J T, Mahasreshti P J, Barker S D, Straughn M, Barnes M N, Alvarez R D, Hemminki A, Curiel D T. Targeting adenovirus to the serotype 3 receptor increases gene transfer efficiency to ovarian cancer cells.  Clin Cancer Res. 2002;  8 275-280
    PubMedGoogle Scholar
  • 3 Kanerva A, Wang M, Bauerschmitz G J, Lam J T, Desmond R A, Bhoola S M, Barnes M N, Alvarez R D, Siegal G P, Curiel D T, Hemminki A. Gene transfer to ovarian cancer versus normal tissues with fiber-modified adenoviruses.  Mol Ther. 2002;  5 695-704
    CrossrefPubMedGoogle Scholar
  • 4 Vanderkwaak T J, Wang M, Gomez-Navarro J, Rancourt C, Dmitriev I, Krasnykh V, Barnes M, Siegal G P, Alvarez R, Curiel D T. An advanced generation of adenoviral vectors selectively enhances gene transfer for ovarian cancer gene therapy approaches.  Gynecol Oncol. 1999;  74 227-234
    CrossrefPubMedGoogle Scholar
  • 5 Chung I, Schwartz P E, Crystal R G, Pizzorno G, Leavitt J, Deisseroth A B. Use of L-plastin promoter to develop an adenoviral system that confers transgene expression in ovarian cancer cells but not in normal mesothelial cells.  Cancer Gene Therapy. 1999;  6 99-106
    CrossrefPubMedGoogle Scholar
  • 6 Casado E, Gomez-Navarro J, Yamamoto M, Adachi Y, Coolidge C J, Arafat W O, Barker S D, Wang M H, Mahasreshti P J, Hemminki A, Gonzalez-Baron M, Barnes M N, Pustilnik T B, Siegal G P, Alvarez R D, Curiel D T. Strategies to accomplish targeted expression of transgenes in ovarian cancer for molecular therapeutic applications.  Clin Cancer Res. 2001;  7 2496-2504
    PubMedGoogle Scholar
  • 7 Breidenbach M, Rein D T, Schondorf T, Khan K N, Herrmann I, Schmidt T, Reynolds P N, Vlodavsky I, Haviv Y S, Curiel D T. A new targeting approach for breast cancer gene therapy using the heparanase promoter.  Cancer Lett. 2006;  240 114-122
    PubMedGoogle Scholar
  • 8 Rein D T, Breidenbach M, Kirby T O, Han T, Siegal G P, Bauerschmitz G J, Wang M, Nettelbeck D M, Tsuruta Y, Yamamoto M, Dall P, Hemminki A, Curiel D T. A fiber-modified, secretory leukoprotease inhibitor promoter-based conditionally replicating adenovirus for treatment of ovarian cancer.  Clin Cancer Res. 2005;  11 1327-1335
    PubMedGoogle Scholar
  • 9 Breidenbach M, Rein D. Gentherapie - eine neue Therapieoption in der Behandlung gynäkologischer Malignome?.  Geburtsh Frauenheilk. 2005;  65 1127-1129
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Wen W H, Reles A, Runnebaum I B, Sullivan-Halley J, Bernstein L, Jones L A, Felix J C, Kreienberg R, el-Naggar A, Press M F. p 53 mutations and expression in ovarian cancers: correlation with overall survival.  Int J Gynecol Pathol. 1999;  18 29-41
    PubMedGoogle Scholar
  • 11 Shahin M S, Hughes J H, Sood A K, Buller R E. The prognostic significance of p 53 tumor suppressor gene alterations in ovarian carcinoma.  Cancer. 2000;  89 2006-2017
    CrossrefPubMedGoogle Scholar
  • 12 Kim J, Hwang E S, Kim J S, You E H, Lee S H, Lee J H. Intraperitoneal gene therapy with adenoviral-mediated p 53 tumor suppressor gene for ovarian cancer model in nude mouse.  Cancer Gene Therapy. 1999;  6 172-178
    CrossrefPubMedGoogle Scholar
  • 13 Kim J, Hwang E S, Kim J S, You E H, Lee S H, Lee J H. Intraperitoneal gene therapy with adenoviral-mediated p 53 tumor suppressor gene for ovarian cancer model in nude mouse.  Cancer Gene Ther. 1999;  6 172-178
    CrossrefPubMedGoogle Scholar
  • 14 Wolf J K, Mills G B, Bazzet L, Bast Jr. R C, Roth J A, Gershenson D M. Adenovirus-mediated p 53 growth inhibition of ovarian cancer cells is independent of endogenous p 53 status.  Gynecol Oncol. 1999;  75 261-266
    CrossrefPubMedGoogle Scholar
  • 15 Buller R E, Runnebaum I B, Karlan B Y, Horowitz J A, Shahin M, Buekers T, Petrauskas S, Kreienberg R, Slamon D, Pegram M. A phase I/II trial of rAd/p 53 (SCH 58500) gene replacement in recurrent ovarian cancer.  Cancer Gene Ther. 2002;  9 553-566
    CrossrefPubMedGoogle Scholar
  • 16 Zeimet A G, Marth C. Why did p 53 gene therapy fail in ovarian cancer?.  Lancet Oncol. 2003;  4 415-422
    CrossrefPubMedGoogle Scholar
  • 17 Tait D L, Obermiller P S, Hatmaker A R, Redlin-Frazier S, Holt J T. Ovarian cancer BRCA1 gene therapy: Phase I and II trial differences in immune response and vector stability.  Clin Cancer Res. 1999;  5 1708-1714
    PubMedGoogle Scholar
  • 18 Deshane J, Loechel F, Conry R M, Siegal G P, King C R, Curiel D T. Intracellular single-chain antibody directed against erbB2 down-regulates cell surface erbB2 and exhibits a selective anti-proliferative effect in erbB2 overexpressing cancer cell lines.  Gene Therapy. 1994;  1 332-337
    PubMedGoogle Scholar
  • 19 Slamon D J, Godolphin W, Jones L A, Holt J A, Wong S G, Keith D E, Levin W J, Stuart S G, Udove J, Ullrich A. et al . Studies of the HER‐2/neu proto-oncogene in human breast and ovarian cancer.  Science. 1989;  244 707-712
    CrossrefPubMedGoogle Scholar
  • 20 Deshane J, Cabrera G, Grim J E, Siegal G P, Pike J, Alvarez R D, Curiel D T. Targeted eradication of ovarian cancer mediated by intracellular expression of anti-erbB‐2 single-chain antibody [see comments].  Gynecologic Oncology. 1995;  59 8-14
    CrossrefPubMedGoogle Scholar
  • 21 Deshane J, Siegal G P, Wang M, Wright M, Bucy R P, Alvarez R D, Curiel D T. Transductional efficacy and safety of an intraperitoneally delivered adenovirus encoding an anti-erbB‐2 intracellular single-chain antibody for ovarian cancer gene therapy.  Gynecologic Oncology. 1997;  64 378-385
    CrossrefPubMedGoogle Scholar
  • 22 Alvarez R D, Barnes M N, Gomez-Navarro J, Wang M, Strong T V, Arafat W, Arani R B, Johnson M R, Roberts B L, Siegal G P, Curiel D T. A cancer gene therapy approach utilizing an anti-erbB‐2 single-chain antibody-encoding adenovirus (AD21): a phase I trial.  Clin Cancer Res. 2000;  6 3081-3087
    PubMedGoogle Scholar
  • 23 Rosenfeld M E, Wang M, Siegal G P, Alvarez R D, Mikheeva G, Krasnykh V, Curiel D T. Adenoviral-mediated delivery of herpes simplex virus thymidine kinase results in tumor reduction and prolonged survival in a SCID mouse model of human ovarian carcinoma.  J Mol Med. 1996;  74 455-462
    CrossrefPubMedGoogle Scholar
  • 24 Tong X W, Block A, Chen S H, Contant C F, Agoulnik I, Blankenburg K, Kaufman R H, Woo S L, Kieback D G. In vivo gene therapy of ovarian cancer by adenovirus-mediated thymidine kinase gene transduction and ganciclovir administration.  Gynecologic Oncology. 1996;  61 175-179
    CrossrefPubMedGoogle Scholar
  • 25 Alvarez R D, Gomez-Navarro J, Wang M, Barnes M N, Strong T V, Arani R B, Arafat W, Hughes J V, Siegal G P, Curiel D T. Adenoviral-mediated suicide gene therapy for ovarian cancer.  Mol Ther. 2000;  2 524-530
    CrossrefPubMedGoogle Scholar
  • 26 Hasenburg A, Tong X W, Rojas-Martinez A, Nyberg-Hoffman C, Kieback C C, Kaplan A, Kaufman R H, Ramzy I, Aguilar-Cordova E, Kieback D G. Thymidine kinase gene therapy with concomitant topotecan chemotherapy for recurrent ovarian cancer.  Cancer Gene Ther. 2000;  7 839-844
    CrossrefPubMedGoogle Scholar
  • 27 Hasenburg A, Tong X W, Fischer D C, Rojas-Martinez A, Nyberg-Hoffman C, Kaplan A L, Kaufman R H, Ramzy I, Aguilar-Cordova E, Kieback D G. Adenovirus-mediated thymidine kinase gene therapy in combination with topotecan for patients with recurrent ovarian cancer: 2.5-year follow-up.  Gynecol Oncol. 2001;  83 549-554
    CrossrefPubMedGoogle Scholar
  • 28 Boocock C A, Charnock-Jones D S, Sharkey A M, McLaren J, Barker P J, Wright K A, Twentyman P R, Smith S K. Expression of vascular endothelial growth factor and its receptors flt and KDR in ovarian carcinoma.  J Natl Cancer Inst. 1995;  87 506-516
    CrossrefPubMedGoogle Scholar
  • 29 de Vries C, Escobedo J A, Ueno H, Houck K, Ferrara N, Williams L T. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor.  Science. 1992;  255 989-991
    PubMedGoogle Scholar
  • 30 Mahasreshti P J, Navarro J G, Kataram M, Wang M H, Carey D, Siegal G P, Barnes M N, Nettelbeck D M, Alvarez R D, Hemminki A, Curiel D T. Adenovirus-mediated soluble FLT‐1 gene therapy for ovarian carcinoma.  Clin Cancer Res. 2001;  7 2057-2066
    PubMedGoogle Scholar
  • 31 Alemany R, Balague C, Curiel D T. Replicative adenoviruses for cancer therapy.  Nat Biotechnol. 2000;  18 723-727
    PubMedGoogle Scholar
  • 32 Vasey P A, Shulman L N, Campos S, Davis J, Gore M, Johnston S, Kirn D H, O'Neill V, Siddiqui N, Seiden M V, Kaye S B. Phase I trial of intraperitoneal injection of the E1B‐55-kd-gene-deleted adenovirus ONYX‐015 (dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer.  J Clin Oncol. 2002;  20 1562-1569
    CrossrefPubMedGoogle Scholar
  • 33 Bauerschmitz G J, Lam J T, Kanerva A, Suzuki K, Nettelbeck D M, Dmitriev I, Krasnykh V, Mikheeva G V, Barnes M N, Alvarez R D, Dall P, Alemany R, Curiel D T, Hemminki A. Treatment of ovarian cancer with a tropism modified oncolytic adenovirus.  Cancer Res. 2002;  62 1266-1270
    PubMedGoogle Scholar
  • 34 Lam J T, Bauerschmitz G J, Kanerva A, Barker S D, Straughn J M, Wang M, Barnes M N, Blackwell J L, Siegal G P, Alvarez R D, Curiel D T, Hemminki A. Replication of an integrin targeted conditionally replicating adenovirus on primary ovarian cancer spheroids.  Cancer Gene Ther. 2003;  10 377-387
    CrossrefPubMedGoogle Scholar
  • 35 Raki M, Rein D T, Kanerva A, Hemminki A. Gene transfer approaches for gynecological diseases.  Mol Ther. 2006;  14 154-163
    CrossrefPubMedGoogle Scholar
  • 36 Carson A, Wang Z, Xiao X, Khan S A. A DNA recombination-based approach to eliminate papillomavirus infection.  Gene Ther. 2005;  12 534-540
    CrossrefPubMedGoogle Scholar
  • 37 Rein D T, Breidenbach M, Nettelbeck D M, Kawakami Y, Siegal G P, Huh W K, Wang M, Hemminki A, Bauerschmitz G J, Yamamoto M, Adachi Y, Takayama K, Dall P, Curiel D T. Evaluation of tissue-specific promoters in carcinomas of the cervix uteri.  J Gene Med. 2004;  6 1281-1289
    CrossrefPubMedGoogle Scholar
  • 38 Das S, Somasundaram K. Therapeutic potential of an adenovirus expressing p 73 beta, a p 53 homologue, against human papilloma virus positive cervical cancer in vitro and in vivo.  Cancer Biol Ther. 2006;  5 210-217
    PubMedGoogle Scholar
  • 39 Immonen A, Vapalahti M, Tyynela K, Hurskainen H, Sandmair A, Vanninen R, Langford G, Murray N, Yla-Herttuala S. AdvHSV‐tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study.  Mol Ther. 2004;  10 967-972
    CrossrefPubMedGoogle Scholar
  • 40 Puumalainen A M, Vapalahti M, Agrawal R S, Kossila M, Laukkanen J, Lehtolainen P, Viita H, Paljarvi L, Vanninen R, Yla-Herttuala S. Beta-galactosidase gene transfer to human malignant glioma in vivo using replication-deficient retroviruses and adenoviruses.  Hum Gene Ther. 1998;  9 1769-1774
    PubMedGoogle Scholar

Daniel T. Rein

Universitätsfrauenklinik Düsseldorf

Moorenstraße 5

40225 Düsseldorf

Email: rein@med.uni-duesseldorf.de