C.B. would like to thank the Engineering and Physical Sciences Research Council for PhD CASE Studentship for this work and Biocompatibles UK Ltd for industrial sponsorship. The authors would like to thank EPO-GmbH for carrying out the ectopic xenograft study.
A.L.L. is a paid employee of Biocompatibles UK Ltd, the sponsor of a PhD CASE studentship for C.B. that generated the data in this manuscript. For the remaining authors, there are no conflicts of interest.
1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55:74–108.
2. Bruix J, Sala M, Llovet JM. Chemoembolization for hepatocellular carcinoma. Gastroenterology 2004; 127 (Suppl 1):S179–S188.
3. Ackerman NB. Experimental studies on the circulation dynamics of intrahepatic tumor blood supply. Cancer 1972; 29:435–439.
4. Breedis C, Young G. The blood supply of neoplasms in the liver. Am J Pathol 1954; 30:969–977.
5. Varela M, Real MI, Burrel M, Forner A, Sala M, Brunet M, et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin
pharmacokinetics. J Hepatol 2007; 46:474–481.
6. Lammer J, Malagari K, Vogl T, Pilleul F, Denys A, Watkinson A, et al. PRECISION V Investigators. Prospective randomized study of doxorubicin
-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol 2010; 33:41–52.
7. Lewis AL, Holden RR. DC Bead embolic drug-eluting bead: clinical application in the locoregional treatment of tumours. Expert Opin Drug Deliv 2011; 8:153–169.
8. Lewis AL, Gonzalez MR, Lloyd AW, Hall B, Tang Y, Willis SL, et al. DC Bead: in vitro characterization of a drug-delivery device for transarterial chemoembolization
. J Vasc Interv Radiol 2006; 17 (Pt 1):335–342.
9. Kerbel RS. Tumor angiogenesis: past, present and the near future. Carcinogenesis 2000; 21:505–515.
10. Semenza GL. Hypoxia
and cancer. Cancer Metastasis Rev 2007; 26:213–214.
11. Semenza GL. HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia
to the nucleus. Cell 2001; 107:1–3.
12. Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia
-inducible factor. Genes Dev 2002; 16:1466–1471.
13. Wang B, Xu H, Gao ZQ, Ning HF, Sun YQ, Cao GW. Increased expression of vascular endothelial growth factor in hepatocellular carcinoma after transcatheter arterial chemoembolization. Acta Radiol 2008; 49:523–529.
14. Li X, Feng GS, Zheng CS, Zhuo CK, Liu X. Expression of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma and effect of transcatheter arterial chemoembolization therapy on plasma vascular endothelial growth factor level. World J Gastroenterol 2004; 10:2878–2882.
15. Virmani S, Rhee TK, Ryu RK, Sato KT, Lewandowski RJ, Mulcahy MF, et al. Comparison of hypoxia
-inducible factor-1alpha expression before and after transcatheter arterial embolization in rabbit VX2 liver tumors. J Vasc Interv Radiol 2008; 19:1483–1489.
16. Semenza GL, Agani F, Booth G, Forsythe J, Iyer N, Jiang BH, et al. Structural and functional analysis of hypoxia
-inducible factor 1. Kidney Int 1997; 51:553–555.
17. Aubel-Sadron G, Londos-Gagliardi D. Daunorubicin and doxorubicin
, anthracycline antibiotics, a physicochemical and biological review. Biochimie 1984; 66:333–352.
18. Keizer HG, Pinedo HM, Schuurhuis GJ, Joenje H. Doxorubicin
(adriamycin): a critical review of free radical-dependent mechanisms of cytotoxicity. Pharmacol Ther 1990; 47:219–231.
19. Zunino F, Capranico G. DNA topoisomerase II as the primary target of anti-tumor anthracyclines. Anticancer Drug Des 1990; 5:307–317.
20. Lee K, Qian DZ, Rey S, Wei H, Liu JO, Semenza GL. Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc Natl Acad Sci USA 2009; 106:2353–2358.
21. Sahin F, Kannangai R, Adegbola O, Wang J, Su G, Torbenson M. mTOR
and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 2004; 10:8421–8425.
22. Land SC, Tee AR. Hypoxia
-inducible factor 1alpha is regulated by the mammalian target of rapamycin
) via an mTOR
signaling motif. J Biol Chem 2007; 282:20534–20543.
23. Rizell M, Andersson M, Cahlin C, Hafström L, Olausson M, Lindnér P. Effects of the mTOR
inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer. Int J Clin Oncol 2008; 13:66–70.
24. Wang W, Jia WD, Xu GL, Wang ZH, Li JS, Ma JL, et al. Antitumoral activity of rapamycin
mediated through inhibition of HIF-1alpha and VEGF in hepatocellular carcinoma. Dig Dis Sci 2009; 54:2128–2136.
25. Wang Z, Zhou J, Fan J, Tan CJ, Qiu SJ, Yu Y, et al. Sirolimus inhibits the growth and metastatic progression of hepatocellular carcinoma. J Cancer Res Clin Oncol 2009; 135:715–722.
26. Wang Z, Zhou J, Fan J, Qiu SJ, Yu Y, Huang XW, Tang ZY. Effect of rapamycin
alone and in combination with sorafenib in an orthotopic model of human hepatocellular carcinoma. Clin Cancer Res 2008; 14:5124–5130.
27. Semela D, Piguet AC, Kolev M, Schmitter K, Hlushchuk R, Djonov V, et al. Vascular remodeling and antitumoral effects of mTOR
inhibition in a rat model of hepatocellular carcinoma. J Hepatol 2007; 46:840–848.
28. Heuer M, Benkö T, Cicinnati VR, Kaiser GM, Sotiropoulos GC, Baba HA, et al. Effect of low-dose rapamycin
on tumor growth in two human hepatocellular cancer cell lines. Transplant Proc 2009; 41:359–365.
29. Huynh H, Chow PK, Palanisamy N, Salto-Tellez M, Goh BC, Lee CK, et al. Bevacizumab and rapamycin
induce growth suppression in mouse models of hepatocellular carcinoma. J Hepatol 2008; 49:52–60.
30. Zhang JF, Liu JJ, Lu MQ, Cai CJ, Yang Y, Li H, et al. Rapamycin
inhibits cell growth by induction of apoptosis on hepatocellular carcinoma cells in vitro. Transpl Immunol 2007; 17:162–168.
31. O’Reilly T, McSheehy PM, Wartmann M, Lassota P, Brandt R, Lane HA. Evaluation of the mTOR
inhibitor, everolimus, in combination with cytotoxic antitumor agents using human tumor models in vitro and in vivo. Anticancer Drugs 2011; 22:58–78.
32. Piguet AC, Semela D, Keogh A, Wilkens L, Stroka D, Stoupis C, et al. Inhibition of mTOR
in combination with doxorubicin
in an experimental model of hepatocellular carcinoma. J Hepatol 2008; 49:78–87.
33. Grunwald V, DeGraffenried L, Russel D, Friedrichs WE, Ray RB, Hidalgo M. Inhibitors of mTOR
resistance conferred by PTEN status in prostate cancer cells. Cancer Res 2002; 62:6141–6145.
34. Forster RE, Tang Y, Bowyer C, Lloyd AW, Macfarlane W, Phillips GJ, Lewis AL. Development of a combination drug-eluting bead: towards enhanced efficacy for locoregional tumour therapies. Anticancer Drugs 2012; 23:355–369.
35. Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 1989; 49:6449–6465.
36. Namur J, Wassef M, Millot JM, Lewis AL, Manfait M, Laurent A. Drug-eluting beads for liver embolization: concentration of doxorubicin
in tissue and in beads in a pig model. J Vasc Interv Radiol 2010; 21:259–267.
37. Namur J, Citron SJ, Sellers MT, Dupuis MH, Wassef M, Manfait M, Laurent A. Embolization of hepatocellular carcinoma with drug-eluting beads: doxorubicin
tissue concentration and distribution in patient liver explants. J Hepatol 2011; 55:1332–1338.
38. Dreher MR, Sharma KV, Woods DL, Reddy G, Tang Y, Pritchard WF, et al. Radiopaque drug-eluting beads for transcatheter embolotherapy: experimental study of drug penetration and coverage in swine. J Vasc Interv Radiol 2012; 23:257–264.
39. Sutherland RM. Cell and environment interactions in tumor microregions: the multicell spheroid model. Science 1988; 240:177–184.
40. Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP. Hypoxia
-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 2002; 62:3387–3394.
41. Ding Z, Yang L, Xie X, Xie F, Pan F, Li J, et al. Expression and significance of hypoxia
-inducible factor-1 alpha and MDR1/P-glycoprotein in human colon carcinoma tissue and cells. J Cancer Res Clin Oncol 2010; 136:1697–1707.
42. Zhu H, Chen XP, Luo SF, Guan J, Zhang WG, Zhang BX. Involvement of hypoxia
-inducible factor-1-alpha in multidrug resistance induced by hypoxia
cells. J Exp Clin Cancer Res 2005; 24:565–574.
43. Dong Z, Wang JZ, Yu F, Venkatachalam MA. Apoptosis-resistance of hypoxic cells: multiple factors involved and a role for IAP-2. Am J Pathol 2003; 163:663–671.
44. Tomida A, Tsuruo T. Drug resistance mediated by cellular stress response to the microenvironment of solid tumors. Anticancer Drug Des 1999; 14:169–177.
45. Ogiso Y, Tomida A, Tsuruo T. Nuclear localization of proteasomes participates in stress-inducible resistance of solid tumor cells to topoisomerase II-directed drugs. Cancer Res 2002; 62:5008–5012.
46. Rharass T, Vigo J, Salmon JM, Ribou AC. New method for the detection of reactive oxygen species in anti-tumoural activity of adriamycin: a comparison between hypoxic and normoxic cells. Free Radic Res 2008; 42:124–134.
47. Gewirtz DA. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 1999; 57:727–741.
48. McClendon AK, Osheroff N. DNA topoisomerase II, genotoxicity and cancer. Mutat Res 2007; 623:83–97.
49. Potmesil M, Kirschenbaum S, Israel M, Levin M, Khetarpal VK, Silber R. Relationship of adramycin concentrations to the DNA lesions induced in hypoxic and euoxic L1210 cells. Cancer Res 1983; 43:3528–3533.
50. Gerwick LE, Kozin SV, Stocks SJ. The pH partition theory predicts the accumulation and toxicity of doxorubicin
in normal and low-pH-adapted cells. Br J Cancer 1999; 79:838–842.
51. Gerwick LE, Vijayappa S, Kozin S. Tumour pH controls the in vivo efficacy of weak acid and base chemotherapeutics. Mol Cancer Ther 2006; 5:1275–1279.
52. Mellor HR, Callaghan R. Accumulation and distribution of doxorubicin
in tumour spheroids: the influence of acidity and expression of P-glycoprotein. Cancer Chemother Pharmacol 2011; 68:1179–1190.
53. Hoof T, Demmer A, Christians U, Tümmler B. Reversal of multidrug resistance in Chinese hamster ovary cells by the immunosuppressive agent rapamycin
. Eur J Pharmacol 1993; 246:53–58.
54. Arceci RJ, Stieglitz K, Bierer BE. Immunosuppressants FK506 and rapamycin
function as reversal agents of the multidrug resistance phenotype. Blood 1992; 80:1528–1536.
55. Pawarode A, Shukla S, Minderman H, Fricke SM, Pinder EM, O’Loughlin KL, et al. Differential effects of the immunosuppressive agents cyclosporin A, tacrolimus and sirolimus on drug transport by multidrug resistance proteins. Cancer Chemother Pharmacol 2007; 60:179–188.