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Combining functional imaging and interstitial pressure measurements to evaluate two anti-angiogenic treatments

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Summary

Background: Interstitial hypertension is responsible for poor capillary blood flow and hampered drug delivery. The efficacy of combined sorafenib/bevacizumab treatment given according to different administration schedules has been evaluated by measuring both interstitial pressure (IP) and quantitative dynamic contrast-enhanced ultrasonography (DCE-US) parameters in melanoma-bearing mice. Materiel and Methods: Sixty mice were xenografted with B16F10 melanoma. Animals received a daily administration over 4 days (D0 to D3) of either sorafenib at 30 mg/kg, bevacizumab at 2.5 mg/kg alone, or different schedules of combined treatments. Perfusion parameters determined using an Aplio® sonograph (Toshiba) with SonoVue® contrast agent (Bracco) were compared to IP measurements using fiberoptic probes (Samba®) at D0, D2, D4, D8. Results: The mean baseline IP values ranged between 6.55 and 31.29 mmHg in all the groups. A transient IP decrease occurred at D2 in all treated groups, and especially in the concomitant group which exhibited a significant IP reduction compared to D0. A significant decrease in both the peak intensity and the area under the curve was observed at D4 in the group with concomitant administration of both molecules which yielded maximal inhibition of the tumor volume and the number of vessels. No correlation was found between IP values and volume or perfusion parameters, indicating complex relationships between IP and vascularization. No IP gradients were found between the center and the periphery but IP values in these two regions were significantly correlated (R = 0.93). Conclusion: The results suggest that IP variations could be predictive of vascular changes and that one single IP measurement is sufficient to fully characterize the whole tumor.

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Abbreviations

IP:

Interstitial Pressure

DCE-US:

Dynamic Contrast-Enhanced Ultrasonography

References

  1. Young JS, Lumsden CE, Stalker AL (1950) The significance of the tissue pressure of normal testicular and of neoplastic (Brown-Pearce carcinoma) tissue in the rabbit. J Pathol Bacteriol 62(3):313–333

    Article  PubMed  CAS  Google Scholar 

  2. Gullino PM, Clark SH, Grantham FH (1964) The interstitial fluid of solid tumors. Cancer Res 24:780–794

    PubMed  CAS  Google Scholar 

  3. Boucher Y, Kirkwood JM, Opacic D, Desantis M, Jain RK (1991) Interstitial hypertension in superficial metastatic melanomas in humans. Cancer Res 51(24):6691–6694

    PubMed  CAS  Google Scholar 

  4. Jain RK (1988) Determinants of tumor blood flow: a review. Cancer Res 48(10):2641–2658

    PubMed  CAS  Google Scholar 

  5. Sevick EM, Jain RK (1989) Geometric resistance to blood flow in solid tumors perfused ex vivo: effects of tumor size and perfusion pressure. Cancer Res 49(13):3506–3512

    PubMed  CAS  Google Scholar 

  6. Heldin CH, Rubin K, Pietras K, Ostman A (2004) High interstitial fluid pressure—an obstacle in cancer therapy. Nat Rev Cancer 4(10):806–813

    Article  PubMed  CAS  Google Scholar 

  7. Jain RK (1987) Transport of molecules in the tumor interstitium: a review. Cancer Res 47(12):3039–3051

    PubMed  CAS  Google Scholar 

  8. Curti BD, Urba WJ, Alvord WG et al (1993) Interstitial pressure of subcutaneous nodules in melanoma and lymphoma patients: changes during treatment. Cancer Res 53(10 Suppl):2204–2207

    PubMed  CAS  Google Scholar 

  9. Milosevic M, Fyles A, Hedley D et al (2001) Interstitial fluid pressure predicts survival in patients with cervix cancer independent of clinical prognostic factors and tumor oxygen measurements. Cancer Res 61(17):6400–6405

    PubMed  CAS  Google Scholar 

  10. Milosevic M, Fyles A, Hedley D, Hill R (2004) The human tumor microenvironment: invasive (needle) measurement of oxygen and interstitial fluid pressure. Semin Radiat Oncol 14(3):249–258

    Article  PubMed  Google Scholar 

  11. Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7(9):987–989

    Article  PubMed  CAS  Google Scholar 

  12. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62

    Article  PubMed  CAS  Google Scholar 

  13. Sorensen AG, Patel S, Harmath C et al (2001) Comparison of diameter and perimeter methods for tumor volume calculation. J Clin Oncol 19(2):551–557

    PubMed  CAS  Google Scholar 

  14. Lassau N, Mercier S, Koscielny S et al (1999) Prognostic value of high-frequency sonography and color Doppler sonography for the preoperative assessment of melanomas. AJR Am J Roentgenol 172(2):457–461

    PubMed  CAS  Google Scholar 

  15. Lassau N, Paturel-Asselin C, Guinebretiere JM et al (1999) New hemodynamic approach to angiogenesis: color and pulsed Doppler ultrasonography. Invest Radiol 34(3):194–198

    Article  PubMed  CAS  Google Scholar 

  16. Lavisse S, Lejeune P, Rouffiac V et al (2008) Early quantitative evaluation of a tumor vasculature disruptive agent AVE8062 using dynamic contrast-enhanced ultrasonography. Invest Radiol 43(2):100–111

    Article  PubMed  CAS  Google Scholar 

  17. Elie N, Kaliski A, Peronneau P, Opolon P, Roche A, Lassau N (2007) Methodology for quantifying interactions between perfusion evaluated by DCE-US and hypoxia throughout tumor growth. Ultrasound Med Biol 33(4):549–560

    Article  PubMed  Google Scholar 

  18. Rouffiac V, Duret JS, Peronneau P et al (2006) Combination of HIFU therapy with contrast-enhanced sonography for quantitative assessment of therapeutic efficiency on tumor grafted mice. Ultrasound Med Biol 32(5):729–740

    Article  PubMed  Google Scholar 

  19. Wilhelm S, Chien DS (2002) BAY 43-9006: preclinical data. Curr Pharm Des 8(25):2255–2257

    Article  PubMed  CAS  Google Scholar 

  20. Murphy DA, Makonnen S, Lassoued W, Feldman MD, Carter C, Lee WM (2006) Inhibition of tumor endothelial ERK activation, angiogenesis, and tumor growth by sorafenib (BAY43-9006). Am J Pathol 169(5):1875–1885

    Article  PubMed  CAS  Google Scholar 

  21. Ferrara N, Hillan KJ, Novotny W (2005) Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 333(2):328–335

    Article  PubMed  CAS  Google Scholar 

  22. Chang YS, Adnane J, Trail PA et al (2007) Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol 59(5):561–574

    Article  PubMed  CAS  Google Scholar 

  23. Liu L, Cao Y, Chen C et al (2006) Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 66(24):11851–11858

    Article  PubMed  CAS  Google Scholar 

  24. Wilhelm SM, Carter C, Tang L et al (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64(19):7099–7109

    Article  PubMed  CAS  Google Scholar 

  25. Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356(2):125–134

    Article  PubMed  CAS  Google Scholar 

  26. Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390

    Article  PubMed  CAS  Google Scholar 

  27. Kolinsky K, Shen BQ, Zhang YE et al (2009) In vivo activity of novel capecitabine regimens alone and with bevacizumab and oxaliplatin in colorectal cancer xenograft models. Mol Cancer Ther 8(1):75–82

    Article  PubMed  CAS  Google Scholar 

  28. Cusack JC Jr, Liu R, Xia L et al (2006) NPI-0052 enhances tumoricidal response to conventional cancer therapy in a colon cancer model. Clin Cancer Res 12(22):6758–6764

    Article  PubMed  CAS  Google Scholar 

  29. Segerstrom L, Fuchs D, Backman U, Holmquist K, Christofferson R, Azarbayjani F (2006) The anti-VEGF antibody bevacizumab potently reduces the growth rate of high-risk neuroblastoma xenografts. Pediatr Res 60(5):576–581

    Article  PubMed  Google Scholar 

  30. Azad NS, Posadas EM, Kwitkowski VE et al (2008) Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol 26(22):3709–3714

    Article  PubMed  CAS  Google Scholar 

  31. Feldman DR, Baum MS, Ginsberg MS et al (2009) Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 27(9):1432–1439

    Article  PubMed  CAS  Google Scholar 

  32. Lassau N, Chami L, Benatsou B, Peronneau P, Roche A (2007) Dynamic contrast-enhanced ultrasonography (DCE-US) with quantification of tumor perfusion: a new diagnostic tool to evaluate the early effects of antiangiogenic treatment. Eur Radiol 17(Suppl 6):F89–F98

    PubMed  Google Scholar 

  33. Miller DL, Dou C, Wiggins RC (2007) Doppler mode pulse sequences mitigate glomerular capillary hemorrhage in contrast-aided diagnostic ultrasound of rat kidney. IEEE Trans Ultrason Ferroelectr Freq Control 54(9):1802–1810

    Article  PubMed  Google Scholar 

  34. Hagendoorn J, Tong R, Fukumura D et al (2006) Onset of abnormal blood and lymphatic vessel function and interstitial hypertension in early stages of carcinogenesis. Cancer Res 66(7):3360–3364

    Article  PubMed  CAS  Google Scholar 

  35. Dickson PV, Hamner JB, Sims TL et al (2007) Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin Cancer Res 13(13):3942–3950

    Article  PubMed  CAS  Google Scholar 

  36. Jain RK (2003) Molecular regulation of vessel maturation. Nat Med 9(6):685–693

    Article  PubMed  CAS  Google Scholar 

  37. Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK (2004) Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 64(11):3731–3736

    Article  PubMed  CAS  Google Scholar 

  38. Gerber HP, Ferrara N (2005) Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res 65(3):671–680

    PubMed  CAS  Google Scholar 

  39. Jain RK, Duda DG, Clark JW, Loeffler JS (2006) Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol 3(1):24–40

    Article  PubMed  CAS  Google Scholar 

  40. Soria JC, Sessa C, Perotti A, et al. (2008) A comprehensive study of translational research and safety exploration of the vascular disrupting agent (VDA) AVE8062 in combination with cisplatin administered every 3 weeks to patients with advanced solid tumors. AACR Meeting Abstracts, Apr 2008; LB-302 2008

  41. Fadnes HO, Reed RK, Aukland K (1977) Interstitial fluid pressure in rats measured with a modified wick technique. Microvasc Res 14(1):27–36

    Article  PubMed  CAS  Google Scholar 

  42. Scholander PF, Hargens AR, Miller SL (1968) Negative pressure in the interstitial fluid of animals. Fluid tensions are spectacular in plants; in animals they are elusively small, but just as vital. Science 161(839):321–328

    Article  PubMed  CAS  Google Scholar 

  43. Wiederhielm CA, Woodbury JW, Kirk S, Rushmer RF (1964) Pulsatile pressures in the microcirculation of frog’s mesentery. Am J Physiol 207:173–176

    PubMed  CAS  Google Scholar 

  44. Rofstad EK, Tunheim SH, Mathiesen B et al (2002) Pulmonary and lymph node metastasis is associated with primary tumor interstitial fluid pressure in human melanoma xenografts. Cancer Res 62(3):661–664

    PubMed  CAS  Google Scholar 

  45. Ozerdem U (2009) Measuring interstitial fluid pressure with fiberoptic pressure transducers. Microvasc Res 77(2):226–229

    Article  PubMed  Google Scholar 

  46. Gutmann R, Leunig M, Feyh J et al (1992) Interstitial hypertension in head and neck tumors in patients: correlation with tumor size. Cancer Res 52(7):1993–1995

    PubMed  CAS  Google Scholar 

  47. Jain RK, Baxter LT (1988) Mechanisms of heterogenous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure. Cancer Res 48:7022–7032

    PubMed  CAS  Google Scholar 

  48. Boucher Y, Baxter LT, Jain RK (1990) Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy. Cancer Res 50(15):4478–4484

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. IR4M/UMR 8081, Paris-Sud University, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805, Villejuif, France

    Ingrid Leguerney, Nathalie Lassau, Mélanie Rodrigues, Valérie Rouffiac, Baya Benatsou, Jessie Thalmensi, Pierre Peronneau & Alain Roche

  2. Department of Statistics and Epidemiology, Institut Gustave Roussy, Villejuif, France

    Serge Koscielny

  3. Department of Medicine, Institut Gustave Roussy, Villejuif, France

    Christophe Massard

  4. Experimental Pathology, Institut Gustave Roussy, Villejuif, France

    Olivia Bawa & Paule Opolon

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  1. Ingrid Leguerney
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Correspondence to Ingrid Leguerney.

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Leguerney, I., Lassau, N., Koscielny, S. et al. Combining functional imaging and interstitial pressure measurements to evaluate two anti-angiogenic treatments. Invest New Drugs 30, 144–156 (2012). https://doi.org/10.1007/s10637-010-9543-y

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  • DOI: https://doi.org/10.1007/s10637-010-9543-y

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