Molecular Biology Reports

, Volume 39, Issue 1, pp 157–165 | Cite as

A self-contained enzyme activating prodrug cytotherapy for preclinical melanoma

  • Gwi-Moon Seo
  • Raja Shekar Rachakatla
  • Sivasai Balivada
  • Marla Pyle
  • Tej B. Shrestha
  • Matthew T. Basel
  • Carl Myers
  • Hongwang Wang
  • Masaaki Tamura
  • Stefan H. Bossmann
  • Deryl L. Troyer
Article

Abstract

Gene-directed enzyme prodrug therapy (GDEPT) has been investigated as a means of cancer treatment without affecting normal tissues. This system is based on the delivery of a suicide gene, a gene encoding an enzyme which is able to convert its substrate from non-toxic prodrug to cytotoxin. In this experiment, we have developed a targeted suicide gene therapeutic system that is completely contained within tumor-tropic cells and have tested this system for melanoma therapy in a preclinical model. First, we established double stable RAW264.7 monocyte/macrophage-like cells (Mo/Ma) containing a Tet-On® Advanced system for intracellular carboxylesterase (InCE) expression. Second, we loaded a prodrug into the delivery cells, double stable Mo/Ma. Third, we activated the enzyme system to convert the prodrug, irinotecan, to the cytotoxin, SN-38. Our double stable Mo/Ma homed to the lung melanomas after 1 day and successfully delivered the prodrug-activating enzyme/prodrug package to the tumors. We observed that our system significantly reduced tumor weights and numbers as targeted tumor therapy after activation of the InCE. Therefore, we propose that this system may be a useful targeted melanoma therapy system for pulmonary metastatic tumors with minimal side effects, particularly if it is combined with other treatments.

Keywords

B16-F10 Mouse lung melanoma Mouse monocytes Targeted cell delivery Suicide therapy 

Supplementary material

11033_2011_720_MOESM1_ESM.pptx (3.2 mb)
Supplementary material 1 (PPTX 3302 kb)

References

  1. 1.
    Azrak RG, Cao S, Slocum HK, Toth K, Durrani FA, Yin MB, Pendyala L, Zhang W, McLeod HL, Rustum YM (2004) Therapeutic synergy between irinotecan and 5-fluorouracil against human tumor xenografts. Clin Cancer Res 10:1121–1129PubMedCrossRefGoogle Scholar
  2. 2.
    Rooseboom M, Commandeur JN, Vermeulen NP (2004) Enzyme-catalyzed activation of anticancer prodrugs. Pharmacol Rev 56:53–102PubMedCrossRefGoogle Scholar
  3. 3.
    Friedlos F, Denny WA, Palmer BD, Springer CJ (1997) Mustard prodrugs for activation by Escherichia coli nitroreductase in gene-directed enzyme prodrug therapy. J Med Chem 40:1270–1275PubMedCrossRefGoogle Scholar
  4. 4.
    Greco O, Dachs GU (2001) Gene directed enzyme/prodrug therapy of cancer: historical appraisal and future prospectives. J Cell Physiol 187:22–36PubMedCrossRefGoogle Scholar
  5. 5.
    Liu Y, Miyoshi H, Nakamura M (2007) Nanomedicine for drug delivery and imaging: a promising avenue for cancer therapy and diagnosis using targeted functional nanoparticles. Int J Cancer 120:2527–2537PubMedCrossRefGoogle Scholar
  6. 6.
    Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, Small JE, Herrlinger U, Ourednik V, Black PM, Breakefield XO, Snyder EY (2000) Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci USA 97:12846–12851PubMedCrossRefGoogle Scholar
  7. 7.
    Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M (2002) Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res 62:3603–3608PubMedGoogle Scholar
  8. 8.
    Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira-Hansen M, Bekele BN, Champlin RE, Andreeff M (2004) Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 96:1593–1603PubMedCrossRefGoogle Scholar
  9. 9.
    Rachakatla RS, Marini F, Weiss ML, Tamura M, Troyer D (2007) Development of human umbilical cord matrix stem cell-based gene therapy for experimental lung tumors. Cancer Gene Ther 14:828–835PubMedCrossRefGoogle Scholar
  10. 10.
    Rachakatla RS, Pyle MM, Ayuzawa R, Edwards SM, Marini FC, Weiss ML, Tamura M, Troyer D (2008) Combination treatment of human umbilical cord matrix stem cell-based interferon-beta gene therapy and 5-fluorouracil significantly reduces growth of metastatic human breast cancer in SCID mouse lungs. Cancer Invest 26:662–670PubMedCrossRefGoogle Scholar
  11. 11.
    Ganta C, Chiyo D, Ayuzawa R, Rachakatla R, Pyle M, Andrews G, Weiss M, Tamura M, Troyer D (2009) Rat umbilical cord stem cells completely abolish rat mammary carcinomas with no evidence of metastasis or recurrence 100 days post-tumor cell inoculation. Cancer Res 69:1815–1820PubMedCrossRefGoogle Scholar
  12. 12.
    Arbab AS, Pandit SD, Anderson SA, Yocum GT, Bur M, Frenkel V, Khuu HM, Read EJ, Frank JA (2006) Magnetic resonance imaging and confocal microscopy studies of magnetically labeled endothelial progenitor cells trafficking to sites of tumor angiogenesis. Stem Cells 24:671–678PubMedCrossRefGoogle Scholar
  13. 13.
    De Palma M, Mazzieri R, Politi LS, Pucci F, Zonari E, Sitia G, Mazzoleni S, Moi D, Venneri MA, Indraccolo S, Falini A, Guidotti LG, Galli R, Naldini L (2008) Tumor-targeted interferon-alpha delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell 14:299–311PubMedCrossRefGoogle Scholar
  14. 14.
    Huang B, Desai A, Tang S, Thomas TP, Baker JR Jr (2010) The synthesis of a c(RGDyK) targeted SN38 prodrug with an indolequinone structure for bioreductive drug release. Org Lett 12:1384–1387PubMedCrossRefGoogle Scholar
  15. 15.
    Matsuzaki T, Yokokura T, Mutai M, Tsuruo T (1988) Inhibition of spontaneous and experimental metastasis by a new derivative of camptothecin, CPT-11, in mice. Cancer Chemother Pharmacol 21:308–312PubMedCrossRefGoogle Scholar
  16. 16.
    Arimori K, Kuroki N, Kumamoto A, Tanoue N, Nakano M, Kumazawa E, Tohgo A, Kikuchi M (2001) Excretion into gastrointestinal tract of irinotecan lactone and carboxylate forms and their pharmacodynamics in rodents. Pharm Res 18:814–822PubMedCrossRefGoogle Scholar
  17. 17.
    O’Reilly S, Rowinsky EK (1996) The clinical status of irinotecan (CPT-11), a novel water soluble camptothecin analogue: 1996. Crit Rev Oncol Hematol 24:47–70PubMedCrossRefGoogle Scholar
  18. 18.
    Aboody KS, Bush RA, Garcia E, Metz MZ, Najbauer J, Justus KA, Phelps DA, Remack JS, Yoon KJ, Gillespie S, Kim SU, Glackin CA, Potter PM, Danks MK (2006) Development of a tumor-selective approach to treat metastatic cancer. PLoS One 1:e23PubMedCrossRefGoogle Scholar
  19. 19.
    Danks MK, Morton CL, Krull EJ, Cheshire PJ, Richmond LB, Naeve CW, Pawlik CA, Houghton PJ, Potter PM (1999) Comparison of activation of CPT-11 by rabbit and human carboxylesterases for use in enzyme/prodrug therapy. Clin Cancer Res 5:917–924PubMedGoogle Scholar
  20. 20.
    Danks MK, Yoon KJ, Bush RA, Remack JS, Wierdl M, Tsurkan L, Kim SU, Garcia E, Metz MZ, Najbauer J, Potter PM, Aboody KS (2007) Tumor-targeted enzyme/prodrug therapy mediates long-term disease-free survival of mice bearing disseminated neuroblastoma. Cancer Res 67:22–25PubMedCrossRefGoogle Scholar
  21. 21.
    Humerickhouse R, Lohrbach K, Li L, Bosron WF, Dolan ME (2000) Characterization of CPT-11 hydrolysis by human liver carboxylesterase isoforms hCE-1 and hCE-2. Cancer Res 60:1189–1192PubMedGoogle Scholar
  22. 22.
    Zhang G, Liao Y, Baker I (2010) Surface engineering of core/shell iron/iron oxide nanoparticles from microemulsions for hyperthermia. Mater Sci Eng C 30:92–97CrossRefGoogle Scholar
  23. 23.
    Balivada S, Rachakatla RS, Wang H, Samarakoon TN, Dani RK, Pyle M, Kroh FO, Walker B, Leaym X, Koper OB, Tamura M, Chikan V, Bossmann SH, Troyer DL (2010) A/C magnetic hyperthermia of melanoma mediated by iron(0)/iron oxide core/shell magnetic nanoparticles: a mouse study. BMC Cancer 10:119PubMedCrossRefGoogle Scholar
  24. 24.
    Sawada S, Okajima S, Aiyama R, Nokata K, Furuta T, Yokokura T, Sugino E, Yamaguchi K, Miyasaka T (1991) Synthesis and antitumor activity of 20(S)-camptothecin derivatives: carbamate-linked, water-soluble derivatives of 7-ethyl-10-hydroxycamptothecin. Chem Pharm Bull (Tokyo) 39:1446–1450Google Scholar
  25. 25.
    Sawada S, Yokokura T, Miyasaka T (1995) Synthesis and antitumor activity of A-ring or E-lactone modified water-soluble prodrugs of 20(S)-camptothecin, including development of irinotecan hydrochloride trihydrate (CPT-11). Curr Pharm Design 1:113–132Google Scholar
  26. 26.
    Miyasaka T, Sawada S, Nokata K, Sugino E, Mutai M (1986) Camptothecin derivatives and process for preparing same. US Patent #4,604,463Google Scholar
  27. 27.
    Wu MH, Yan B, Humerickhouse R, Dolan ME (2002) Irinotecan activation by human carboxylesterases in colorectal adenocarcinoma cells. Clin Cancer Res 8:2696–2700PubMedGoogle Scholar
  28. 28.
    Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ (2004) Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 22:1382–1388PubMedCrossRefGoogle Scholar
  29. 29.
    van Ark-Otte J, Kedde MA, van der Vijgh WJ, Dingemans AM, Jansen WJ, Pinedo HM, Boven E, Giaccone G (1998) Determinants of CPT-11 and SN-38 activities in human lung cancer cells. Br J Cancer 77:2171–2176PubMedCrossRefGoogle Scholar
  30. 30.
    Oosterhoff D, Pinedo HM, van der Meulen IH, de Graaf M, Sone T, Kruyt FA, van Beusechem VW, Haisma HJ, Gerritsen WR (2002) Secreted and tumour targeted human carboxylesterase for activation of irinotecan. Br J Cancer 87:659–664PubMedCrossRefGoogle Scholar
  31. 31.
    Bissery MC, Vrignaud P, Lavelle F, Chabot GG (1996) Experimental antitumor activity and pharmacokinetics of the camptothecin analog irinotecan (CPT-11) in mice. Anticancer Drugs 7:437–460PubMedCrossRefGoogle Scholar
  32. 32.
    Bissery MC, Vrignaud P, Lavelle F, Chabot GG (1996) Preclinical antitumor activity and pharmacokinetics of irinotecan (CPT-11) in tumor-bearing mice. Ann N Y Acad Sci 803:173–180PubMedCrossRefGoogle Scholar
  33. 33.
    Kaneda N, Nagata H, Furuta T, Yokokura T (1990) Metabolism and pharmacokinetics of the camptothecin analogue CPT-11 in the mouse. Cancer Res 50:1715–1720PubMedGoogle Scholar
  34. 34.
    Tardi PG, Dos Santos N, Harasym TO, Johnstone SA, Zisman N, Tsang AW, Bermudes DG, Mayer LD (2009) Drug ratio-dependent antitumor activity of irinotecan and cisplatin combinations in vitro and in vivo. Mol Cancer Ther 8:2266–2275PubMedCrossRefGoogle Scholar
  35. 35.
    Zabala M, Wang L, Hernandez-Alcoceba R, Hillen W, Qian C, Prieto J, Kramer MG (2004) Optimization of the Tet-on system to regulate interleukin 12 expression in the liver for the treatment of hepatic tumors. Cancer Res 64:2799–2804PubMedCrossRefGoogle Scholar
  36. 36.
    Reuveni D, Halperin D, Fabian I, Tsarfaty G, Askenasy N, Shalit I (2010) Moxifloxacin increases anti-tumor and anti-angiogenic activity of irinotecan in human xenograft tumors. Biochem Pharmacol 79:1100–1107PubMedCrossRefGoogle Scholar
  37. 37.
    Solinas G, Germano G, Mantovani A, Allavena P (2009) Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 86:1065–1073PubMedCrossRefGoogle Scholar
  38. 38.
    Strik HM, Hulper P, Erdlenbruch B, Meier J, Kowalewski A, Hemmerlein B, Gold R, Bahr M (2006) Models of monocytic invasion into glioma cell aggregates. Anticancer Res 26:865–871PubMedGoogle Scholar
  39. 39.
    Valable S, Barbier EL, Bernaudin M, Roussel S, Segebarth C, Petit E, Remy C (2008) In vivo MRI tracking of exogenous monocytes/macrophages targeting brain tumors in a rat model of glioma. Neuroimage 40:973–983PubMedCrossRefGoogle Scholar
  40. 40.
    Burke B, Sumner S, Maitland N, Lewis CE (2002) Macrophages in gene therapy: cellular delivery vehicles and in vivo targets. J Leukoc Biol 72:417–428PubMedGoogle Scholar
  41. 41.
    Burke B (2003) Macrophages as novel cellular vehicles for gene therapy. Expert Opin Biol Ther 3:919–924PubMedCrossRefGoogle Scholar
  42. 42.
    Burke B, Giannoudis A, Corke KP, Gill D, Wells M, Ziegler-Heitbrock L, Lewis CE (2003) Hypoxia-induced gene expression in human macrophages: implications for ischemic tissues and hypoxia-regulated gene therapy. Am J Pathol 163:1233–1243PubMedCrossRefGoogle Scholar
  43. 43.
    Barthel BL, Zhang Z, Rudnicki DL, Coldren CD, Polinkovsky M, Sun H, Koch GG, Chan DC, Koch TH (2009) Preclinical efficacy of a carboxylesterase 2-activated prodrug of doxazolidine. J Med Chem 52:7678–7688PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Gwi-Moon Seo
    • 1
  • Raja Shekar Rachakatla
    • 1
  • Sivasai Balivada
    • 1
  • Marla Pyle
    • 1
  • Tej B. Shrestha
    • 1
  • Matthew T. Basel
    • 1
  • Carl Myers
    • 2
  • Hongwang Wang
    • 3
  • Masaaki Tamura
    • 1
  • Stefan H. Bossmann
    • 3
  • Deryl L. Troyer
    • 1
  1. 1.Department of Anatomy and Physiology, College of Veterinary MedicineKansas State UniversityManhattanUSA
  2. 2.Department of Diagnostic Medicine/Pathobiology, College of Veterinary MedicineKansas State UniversityManhattanUSA
  3. 3.Department of ChemistryKansas State UniversityManhattanUSA

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