23. Borgnetto ME, Zunino F, Tinelli S, Ka¨s E, Capranico G (1996) Drug-specific sites of topoisomerase II DNA cleavage in Drosophila chromatin: heterogeneous localization and reversibility. Cancer Res 56: 1855–1862. 24. Barret JM, Kruczynski A, Vispe S, Annereau JP, Brel V, et al. (2008) F14512, a potent antitumor agent targeting topoisomerase II vectored into cancer cells via the polyamine transport system. Cancer Res 68: 9845–9853. 25. Kruczynski A, Vandenberghe I, Pillon A, Pesnel S, Goetsch L, et al. (2009) Preclinical activity of F14512, designed to target tumors expressing an active polyamine transport system. Invest New Drugs. 26. Seiler N (2003) Thirty years of polyamine-related approaches to cancer therapy. Retrospect and prospect. Part 1. Selective enzyme inhibitors. Curr Drug Targets 4: 537–564. 27. Hu HY, Liu XX, Jiang CY, Lu Y, Liu SL, et al. (2005) Ornithine decarboxylase gene is overexpressed in colorectal carcinoma. World J Gastroenterol 11: 2244–2248. 28. Mafune K, Tanaka Y, Mimori K, Mori M, Takubo K, et al. (1999) Increased expression of ornithine decarboxylase messenger RNA in human esophageal carcinoma. Clin Cancer Res 5: 4073–4078. 29. Tian H, Huang Q, Li L, Liu XX, Zhang Y (2006) Gene expression of ornithine decarboxylase in lung cancers and its clinical significance. Acta Bioch Bioph Sin (Shanghai) 38: 639–645. 30. Young L, Salomon R, Au W, Allan C, Russell P, et al. (2006) Ornithine decarboxylase (ODC) expression pattern in human prostate tissues and ODC transgenic mice. J Histochem Cytochem 54: 223–229. 31. Casero RA Jr., Woster PM (2009) Recent advances in the development of polyamine analogues as antitumor agents. J Med Chem 52: 4551–4573. 32. Seiler N, Delcros JG, Moulinoux JP (1996) Polyamine transport in mammalian cells. An update. Int J Biochem Cell Biol 28: 843–861. 33. Byl JA, Cline SD, Utsugi T, Kobunai T, Yamada Y, et al. (2001) DNA topoisomerase II as the target for the anticancer drug TOP-53: mechanistic basis for drug action. Biochemistry 40: 712–718. 34. Utsugi T, Shibata J, Sugimoto Y, Aoyagi K, Wierzba K, et al. (1996) Antitumor activity of a novel podophyllotoxin derivative (TOP-53) against lung cancer and lung metastatic cancer. Cancer Res 56: 2809–2814. 35. Imbert T, Guminski Y, Barret JM, Kruczynski A (2005) (Poly) aminoacetamide derivatives of epipodophyllotoxin, their process of preparation and their applications in therapeutics as anticancer agents . 36. Aulner N, Monod C, Mandicourt G, Jullien D, Cuvier O, et al. (2002) The AT- hook protein D1 is essential for Drosophila melanogaster development and is implicated in position-effect variegation. Mol Cell Biol 22: 1218–1232. 37. Ka¨s E, Poljak L, Adachi Y, Laemmli UK (1993) A model for chromatin opening: stimulation of topoisomerase II and restriction enzyme cleavage of chromatin by distamycin. EMBO J 12: 115–126. 38. Fesen M, Pommier Y (1989) Mammalian topoisomerase II activity is modulated by the DNA minor groove binder distamycin in simian virus 40 DNA. J Biol Chem 264: 11354–11359. 39. Blattes R, Monod C, Susbielle G, Cuvier O, Wu JH, et al. (2006) Displacement of D1, HP1 and topoisomerase II from satellite heterochromatin by a specific polyamide. EMBO J 25: 2397–2408. 40. Udvardy A, Schedl P (1991) Chromatin structure, not DNA sequence specificity, is the primary determinant of topoisomerase II sites of action in vivo. Mol Cell Biol 11: 4973–4984. 41. Reymann S, Borlak J (2008) Topoisomerase II inhibition involves characteristic chromosomal expression patterns. BMC Genomics 9: 324. 42. Larsen AK, Escargueil AE, Skladanowski A (2003) From DNA damage to G2 arrest: the many roles of topoisomerase II. Prog Cell Cycle Res 5: 295–300. 43. Lupo R, Breiling A, Bianchi ME, Orlando V (2001) Drosophila chromosome condensation proteins Topoisomerase II and Barren colocalize with Polycomb and maintain Fab-7 PRE silencing. Mol Cell 7: 127–136. 44. Marchion DC, Bicaku E, Daud AI, Sullivan DM, Munster PN (2005) In vivo synergy between topoisomerase II and histone deacetylase inhibitors: predictive correlates. Mol Cancer Ther 4: 1993–2000. 45. Montecucco A, Biamonti G (2007) Cellular response to etoposide treatment. Cancer Lett 252: 9–18. 46. Tanaka T, Halicka HD, Traganos F, Seiter K, Darzynkiewicz Z (2007) Induction of ATM activation, histone H2AX phosphorylation and apoptosis by etoposide: relation to cell cycle phase. Cell Cycle 6: 371–376. 47. Muller HJ (1930) Types of visible variations induced by X-rays in Drosophila. J Genetics 22: 299–333. 48. Fanti L, Pimpinelli S (2008) HP1: a functionally multifaceted protein. Curr Opin Genet Dev 18: 169–174. Studying Anticancer Drug Properties in Drosophila 49. Girton JR, Johansen KM (2008) Chromatin structure and the regulation of gene expression: the lessons of PEV in Drosophila. Adv Genet 61: 1–43. 50. Judd BH (1995) Mutations of zeste that mediate transvection are recessive enhancers of position-effect variegation in Drosophila melanogaster. Genetics 141: 245–253. 51. Chern JJ, Choi KW (2002) Lobe mediates Notch signaling to control domain- specific growth in the Drosophila eye disc. Development 129: 4005–4013. 52. Nakaya MA, Biris K, Tsukiyama T, Jaime S, Rawls JA, et al. (2005) Wnt3a links left-right determination with segmentation and anteroposterior axis elongation. Development 132: 5425–5436. 53. Susbielle G, Blattes R, Brevet V, Monod C, Kas E (2005) Target practice: aiming at satellite repeats with DNA minor groove binders. Curr Med Chem - Anti-Cancer Agents 5: 409–420. 54. Hasinoff BB, Takeda K, Ferrans VJ, Yu ZX (2002) The doxorubicin cardioprotective agent dexrazoxane (ICRF-187) induces endopolyploidy in rat neonatal myocytes through inhibition of DNA topoisomerase II. Anticancer Drugs 13: 255–258. 55. Hasinoff BB, Abram ME, Barnabe N, Khelifa T, Allan WP, et al. (2001) The catalytic DNA topoisomerase II inhibitor dexrazoxane (ICRF-187) induces differentiation and apoptosis in human leukemia K562 cells. Mol Pharmacol 59: 453–461. 56. Yan T, Deng S, Metzger A, Godtel-Armbrust U, Porter AC, et al. (2009) Topoisomerase II{alpha}-dependent and -independent apoptotic effects of dexrazoxane and doxorubicin. Mol Cancer Ther 8: 1075–1085. 57. Gentry AC, Pitts SL, Jablonsky MJ, Bailly C, Graves DE, et al. (2011) Interactions between the etoposide derivative F14512 and human type II topoisomerases: implications for the C4 spermine moiety in promoting enzyme- mediated DNA cleavage. Biochemistry 50: 3240–3249. 58. Wyckoff E, Natalie D, Nolan JM, Lee M, Hsieh T (1989) Structure of the Drosophila DNA topoisomerase II gene. Nucleotide sequence and homology among topoisomerases II. J Mol Biol 205: 1–13. 59. Ju BG, Lunyak VV, Perissi V, Garcia-Bassets I, Rose DW, et al. (2006) A topoisomerase IIbeta-mediated dsDNA break required for regulated transcrip- tion. Science 312: 1798–1802. 60. Fanti L, Berloco M, Pimpinelli S (1994) Carnitine suppression of position-effect variegation in Drosophila melanogaster. Mol Gen Genet 244: 588–595. 61. Janssen S, Cuvier O, Muller M, Laemmli UK (2000) Specific gain- and loss-of- function phenotypes induced by satellite-specific DNA-binding drugs fed to Drosophila melanogaster. Mol Cell 6: 1013–1024. 62. Mottus R, Reeves R, Grigliatti TA (1980) Butyrate suppression of position-effect variegation in Drosophila melanogaster. Mol Gen Genet 178: 465–469. 63. Reuter G, Dorn R, Hoffmann HJ (1982) Butyrate sensitive suppressor of position-effect variegation mutations in Drosophila melanogaster. Mol Gen Genet 188: 480–485. 64. Plaza S, Prince F, Jaeger J, Kloter U, Flister S, et al. (2001) Molecular basis for the inhibition of Drosophila eye development by Antennapedia. EMBO J 20: 802–811. 65. Gindhart JG Jr., Kaufman TC (1995) Identification of Polycomb and trithorax group responsive elements in the regulatory region of the Drosophila homeotic gene Sex combs reduced. Genetics 139: 797–814. 66. Fic W, Juge F, Soret J, Tazi J (2007) Eye development under the control of SRp55/B52-mediated alternative splicing of eyeless. PLoS One 2: e253. 67. Halder G, Callaerts P, Gehring WJ (1995) Induction of ectopic eyes by targeted expression of the eyeless gene in Drosophila. Science 267: 1788–1792. 68. Smith CD, Shu S, Mungall CJ, Karpen GH (2007) The Release 5.1 annotation of Drosophila melanogaster heterochromatin. Science 316: 1586–1591. 69. Sun FL, Cuaycong MH, Craig CA, Wallrath LL, Locke J, et al. (2000) The fourth chromosome of Drosophila melanogaster: interspersed euchromatic and heterochromatic domains. Proc Natl Acad Sci U S A 97: 5340–5345. 70. Huisinga KL, Brower-Toland B, Elgin SC (2006) The contradictory definitions of heterochromatin: transcription and silencing. Chromosoma 115: 110–122. 71. Schultz J (1936) Variegation in Drosophila and the Inert Chromosome Regions. Proc Natl Acad SciUSA 22: 27–33. 72. Tsen C, Iltis M, Kaur N, Bayer C, Delcros JG, et al. (2008) A Drosophila model to identify polyamine-drug conjugates that target the polyamine transporter in an intact epithelium. J Med Chem 51: 324–330. 73. Osman D, Gobert V, Ponthan F, Heidenreich O, Haenlin M, et al. (2009) A Drosophila model identifies calpains as modulators of the human leukemogenic fusion protein AML1-ETO. Proc Natl Acad Sci U S A 106: 12043–12048. 74. Mirkovitch J, Mirault ME, Laemmli UK (1984) Organization of the higher- order chromatin loop: specific DNA attachment sites on nuclear scaffold. Cell 39: 223–232. PLoS ONE | www.plosone.org 15 August 2011 | Volume 6 | Issue 8 | e23597