Investigational New Drugs

, Volume 31, Issue 4, pp 801–811

Therapeutic efficacy of 188Re-liposome in a C26 murine colon carcinoma solid tumor model

  • Ya-Jen Chang
  • Chin-Wei Hsu
  • Chih-Hsien Chang
  • Keng-Li Lan
  • Gann Ting
  • Te-Wei Lee
PRECLINICAL STUDIES

Summary

Nanoliposomes are good drug delivery systems that allow the encapsulation of drugs into vesicles for their delivery. The objective of this study is to investigate the therapeutic efficacy of a new radio-therapeutics of 188Re-labeled pegylated liposome in a C26 murine colon carcinoma solid tumor model. The safety of 188Re-liposome was evaluated before radiotherapy treatment. The anti-tumor effect of 188Re-liposome was assessed by tumor growth inhibition, survival ratio and ultrasound imaging. Apoptotic marker in tumor was also evaluated by the TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling) method after injection of 188Re-liposome. The group treated with 188Re-liposome displayed slight loss in body weight and decrease in white blood cell (WBC) count 7 to 14 days post-injection. With respect to therapeutic efficacy, the tumor-bearing mice treated with 188Re-liposome showed better mean tumor growth inhibition rate (MGI) and longer median survival time (MGI = 0.140; 80 day) than those treated with anti-cancer drug 5-FU (MGI = 0.195; 69 day) and untreated control mice (MGI = 0.413; 48 day). The ultrasound imaging showed a decrease in both tumor volume and number of blood vessels. There were significantly more apoptotic nuclei (TUNEL-positive) in 188Re-liposome-treated mice at 8 h after treatment than in control mice. These results evidenced the potential benefits achieved by oncological application of the radio-therapeutics 188Re-liposome for adjuvant cancer treatment.

Keywords

5-fluorouracil Liposomes Rhenium-188 Colon cancer Radiotherapy 

References

  1. 1.
    Davis ME, Chen ZG, Shin DM (2008) Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev 7:771–782CrossRefGoogle Scholar
  2. 2.
    Cho K, Wang X, Nie S, Chen ZG, Shin DM (2008) Therapeutic nanoparticles for drug delivery in cancer. Clin Cancer Res 14:1310–1316PubMedCrossRefGoogle Scholar
  3. 3.
    Ferrari M (2005) Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer 5:161–171PubMedCrossRefGoogle Scholar
  4. 4.
    Wolpin BM, Meyerhardt JA, Mamon HJ, Mayer RJ (2007) Adjuvant treatment of colorectal cancer. CA Cancer J Clin 57:168–185PubMedCrossRefGoogle Scholar
  5. 5.
    International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators (1995) Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet 345:939–944CrossRefGoogle Scholar
  6. 6.
    Vincent M, Labianca R, Harper P (1999) Which 5-fluorouracil regimen?–the great debate. Anticancer Drugs 10:337–354PubMedCrossRefGoogle Scholar
  7. 7.
    Yoshida M, Hoshi A, Kuretani K (1980) The difference in mechanism of action of 5-fluorouracil and its nucleosides in L5178y cells. J Pharmacobiodyn 3:374–379PubMedCrossRefGoogle Scholar
  8. 8.
    Heidelberger C (1981) On the rational development of a new drug: the example of the fluorinated pyrimidines. Cancer Treat Rep 65(Suppl 3):3–9PubMedGoogle Scholar
  9. 9.
    Nahas A, Savlov ED, Hall TC (1974) Phosphoriboxyl transferase in colon tumor and normal mucosa as an aid in adjuvant chemotherapy with 5-fluorouracil (NSC-19893). Cancer Chemother Rep 58:909–912PubMedGoogle Scholar
  10. 10.
    Nadal JC, van Groeningen CJ, Pinedo HM, Peters GJ (1989) Schedule-dependency of in vivo modulation of 5-fluorouracil by leucovorin and uridine in murine colon carcinoma. Invest New Drugs 7:163–172PubMedCrossRefGoogle Scholar
  11. 11.
    Porschen R, Bermann A, Loffler T, Haack G, Rettig K, Anger Y, Strohmeyer G (2001) Fluorouracil plus leucovorin as effective adjuvant chemotherapy in curatively resected stage III colon cancer: results of the trial adjCCA-01. J Clin Oncol 19:1787–1794PubMedGoogle Scholar
  12. 12.
    Van Cutsem E, Peeters M (1999) Developments in fluoropyrimidine therapy for gastrointestinal cancer. Curr Opin Oncol 11:312–317PubMedCrossRefGoogle Scholar
  13. 13.
    Ewertz M, Holmberg L, Tretli S, Pedersen BV, Kristensen A (2001) Risk factors for male breast cancer–a case–control study from Scandinavia. Acta Oncol 40:467–471PubMedCrossRefGoogle Scholar
  14. 14.
    O’Connell MJ (2004) Current status of adjuvant therapy for colorectal cancer. Oncology (Williston Park) 18:751–755, discussion 5–8Google Scholar
  15. 15.
    Chung KY, Saltz LB (2007) Adjuvant therapy of colon cancer: current status and future directions. Cancer J 13:192–197PubMedCrossRefGoogle Scholar
  16. 16.
    Brannon-Peppas L, Blanchette JO (2004) Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev 56:1649–1659PubMedCrossRefGoogle Scholar
  17. 17.
    Chang YJ, Chang CH, Chang TJ, Yu CY, Chen LC, Jan ML, Luo TY, Lee TW, Ting G (2007) Biodistribution, pharmacokinetics and microSPECT/CT imaging of 188Re-BMEDA-liposome in a C26 murine colon carcinoma solid tumor animal model. Anticancer Res 27:2217–2225PubMedGoogle Scholar
  18. 18.
    Chen LC, Chang CH, Yu CY, Chang YJ, Hsu WC, Ho CL, Yeh CH, Luo TY, Lee TW, Ting G (2007) Biodistribution, pharmacokinetics and imaging of 188Re-BMEDA-labeled pegylated liposomes after intraperitoneal injection in a C26 colon carcinoma ascites mouse model. Nucl Med Biol 34:415–423PubMedCrossRefGoogle Scholar
  19. 19.
    Chen LC, Wu YH, Liu IH, Ho CL, Lee WC, Chang CH, Lan KL, Ting G, Lee TW, Shien JH (2012) Pharmacokinetics, dosimetry and comparative efficacy of 188Re-liposome and 5-FU in a CT26-luc lung-metastatic mice model. Nucl Med Biol 39:35–43PubMedCrossRefGoogle Scholar
  20. 20.
    Tsai CC, Chang CH, Chen LC, Chang YJ, Lan KL, Wu YH, Hsu CW, Liu IH, Ho CL, Lee WC, Ni HC, Chang TJ et al (2012) Biodistribution and pharmacokinetics of 188Re-liposomes and their comparative therapeutic efficacy with 5-fluorouracil in C26 colonic peritoneal carcinomatosis mice. Int J Nanomedicine 6:2607–2619Google Scholar
  21. 21.
    McDonnell TJ, Meyn RE, Robertson LE (1995) Implications of apoptotic cell death regulation in cancer therapy. Semin Cancer Biol 6:53–60PubMedCrossRefGoogle Scholar
  22. 22.
    Bold RJ, Termuhlen PM, McConkey DJ (1997) Apoptosis, cancer and cancer therapy. Surg Oncol 6:133–142PubMedCrossRefGoogle Scholar
  23. 23.
    Rosen EM, Vinter DW, Goldberg ID (1989) Hypertrophy of cultured bovine aortic endothelium following irradiation. Radiat Res 117:395–408PubMedCrossRefGoogle Scholar
  24. 24.
    Dietz A, Delorme S, Rudat V, Zuna I, Conradt C, Vanselow B, Weidauer H (2000) Prognostic assessment of sonography and tumor volumetry in advanced cancer of the head and neck by use of doppler ultrasonography. Otolaryngol Head Neck Surg 122:596–601PubMedGoogle Scholar
  25. 25.
    Lassau N, Lamuraglia M, Vanel D, Le Cesne A, Chami L, Jaziri S, Terrier P, Roche A, Leclere J, Bonvalot S (2005) Doppler US with perfusion software and contrast medium injection in the early evaluation of isolated limb perfusion of limb sarcomas: prospective study of 49 cases. Ann Oncol 16:1054–1060PubMedCrossRefGoogle Scholar
  26. 26.
    Ogura O, Takebayashi Y, Sameshima T, Maeda S, Yamada K, Hata K, Akiba S, Aikou T (2001) Preoperative assessment of vascularity by color Doppler ultrasonography in human rectal carcinoma. Dis Colon Rectum 44:538–546, discussion 46–8PubMedCrossRefGoogle Scholar
  27. 27.
    Bao A, Goins B, Klipper R, Negrete G, Phillips WT (2003) 186Re-liposome labeling using 186Re-SNS/S complexes: in vitro stability, imaging, and biodistribution in rats. J Nucl Med 44:1992–1999PubMedGoogle Scholar
  28. 28.
    Chen LC, Chang CH, Yu CY, Chang YJ, Wu YH, Lee WC, Yeh CH, Lee TW, Ting G (2008) Pharmacokinetics, micro-SPECT/CT imaging and therapeutic efficacy of 188Re-DXR-liposome in C26 colon carcinoma ascites mice model. Nucl Med Biol 35:883–893PubMedCrossRefGoogle Scholar
  29. 29.
    Chang YJ, Chang CH, Yu CY, Chang TJ, Chen LC, Chen MH, Lee TW, Ting G (2010) Therapeutic efficacy and microSPECT/CT imaging of 188Re-DXR-liposome in a C26 murine colon carcinoma solid tumor model. Nucl Med Biol 37:95–104PubMedCrossRefGoogle Scholar
  30. 30.
    Carlsson G, Gullberg B, Hafstrom L (1983) Estimation of liver tumor volume using different formulas - an experimental study in rats. J Cancer Res Clin Oncol 105:20–23PubMedCrossRefGoogle Scholar
  31. 31.
    Fang F, Wang AP, Yang SF (2005) Antitumor activity of a novel recombinant mutant human tumor necrosis factor-related apoptosis-inducing ligand. Acta Pharmacol Sin 26:1373–1381PubMedCrossRefGoogle Scholar
  32. 32.
    Morgillo F, Kim WY, Kim ES, Ciardiello F, Hong WK, Lee HY (2007) Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res 13:2795–2803PubMedCrossRefGoogle Scholar
  33. 33.
    Maddalena ME, Fox J, Chen J, Feng W, Cagnolini A, Linder KE, Tweedle MF, Nunn AD, Lantry LE (2009) 177Lu-AMBA biodistribution, radiotherapeutic efficacy, imaging, and autoradiography in prostate cancer models with low GRP-R expression. J Nucl Med 50:2017–2024PubMedCrossRefGoogle Scholar
  34. 34.
    de Groot JF, Piao Y, Lu L, Fuller GN, Yung WK (2008) Knockdown of GluR1 expression by RNA interference inhibits glioma proliferation. J Neurooncol 88:121–133PubMedCrossRefGoogle Scholar
  35. 35.
    Zavaleta CL, Goins BA, Bao A, McManus LM, McMahan CA, Phillips WT (2008) Imaging of 186Re-liposome therapy in ovarian cancer xenograft model of peritoneal carcinomatosis. J Drug Target 16:626–637PubMedCrossRefGoogle Scholar
  36. 36.
    Liu CM, Chang CH, Chang YJ, Hsu CW, Chen LC, Chen HL, Ho CL, Yu CY, Chang TJ, Chiang TC, Lee TW (2010) Preliminary evaluation of acute toxicity of 188Re-BMEDA-liposome in rats. J Appl Toxicol 30:680–687PubMedCrossRefGoogle Scholar
  37. 37.
    De Ruyck K, Lambert B, Bacher K, Gemmel F, De Vos F, Vral A, de Ridder L, Dierckx RA, Thierens H (2004) Biologic dosimetry of 188Re-HDD/lipiodol versus 131I-lipiodol therapy in patients with hepatocellular carcinoma. J Nucl Med 45:612–618PubMedGoogle Scholar
  38. 38.
    Chen P, Cameron R, Wang J, Vallis KA, Reilly RM (2003) Antitumor effects and normal tissue toxicity of 111In-labeled epidermal growth factor administered to athymic mice bearing epidermal growth factor receptor-positive human breast cancer xenografts. J Nucl Med 44:1469–1478PubMedGoogle Scholar
  39. 39.
    Behr TM, Sgouros G, Stabin MG, Behe M, Angerstein C, Blumenthal RD, Apostolidis C, Molinet R, Sharkey RM, Koch L, Goldenberg DM, Becker W (1999) Studies on the red marrow dosimetry in radioimmunotherapy: an experimental investigation of factors influencing the radiation-induced myelotoxicity in therapy with beta-, Auger/conversion electron-, or alpha-emitters. Clin Cancer Res 5:3031s–3043sPubMedGoogle Scholar
  40. 40.
    Behr TM, Behe M, Sgouros G (2002) Correlation of red marrow radiation dosimetry with myelotoxicity: empirical factors influencing the radiation-induced myelotoxicity of radiolabeled antibodies, fragments and peptides in pre-clinical and clinical settings. Cancer Biother Radiopharm 17:445–464PubMedCrossRefGoogle Scholar
  41. 41.
    Hendry JH, Potten CS (1982) Intestinal cell radiosensitivity: a comparison for cell death assayed by apoptosis or by a loss of clonogenicity. Int J Radiat Biol Relat Stud Phys Chem Med 42:621–628PubMedCrossRefGoogle Scholar
  42. 42.
    Potten CS (1992) The significance of spontaneous and induced apoptosis in the gastrointestinal tract of mice. Cancer Metastasis Rev 11:179–195PubMedCrossRefGoogle Scholar
  43. 43.
    Stephens LC, King GK, Peters LJ, Ang KK, Schultheiss TE, Jardine JH (1986) Unique radiosensitivity of serous cells in rhesus monkey submandibular glands. Am J Pathol 124:479–487PubMedGoogle Scholar
  44. 44.
    Stephens LC, Schultheiss TE, Small SM, Ang KK, Peters LJ (1989) Response of parotid gland organ culture to radiation. Radiat Res 120:140–153PubMedCrossRefGoogle Scholar
  45. 45.
    Dewey WC, Ling CC, Meyn RE (1995) Radiation-induced apoptosis: relevance to radiotherapy. Int J Radiat Oncol Biol Phys 33:781–796PubMedCrossRefGoogle Scholar
  46. 46.
    Verheij M, Bartelink H (2000) Radiation-induced apoptosis. Cell Tissue Res 301:133–142PubMedCrossRefGoogle Scholar
  47. 47.
    Jonathan EC, Bernhard EJ, McKenna WG (1999) How does radiation kill cells? Curr Opin Chem Biol 3:77–83PubMedCrossRefGoogle Scholar
  48. 48.
    Mehrara E, Forssell-Aronsson E, Ahlman H, Bernhardt P (2007) Specific growth rate versus doubling time for quantitative characterization of tumor growth rate. Cancer Res 67:3970–3975PubMedCrossRefGoogle Scholar
  49. 49.
    Sarma HD, Das T, Banerjee S, Venkatesh M, Vidyasagar PB, Mishra KP (2010) Biologic evaluation of a novel 188Re-labeled porphyrin in mice tumor model. Cancer Biother Radiopharm 25:47–54PubMedCrossRefGoogle Scholar
  50. 50.
    Kinuya S, Yokoyama K, Tega H, Hiramatsu T, Konishi S, Watanabe N, Shuke N, Aburano T, Takayama T, Michigishi T, Tonami N (1999) Efficacy, toxicity and mode of interaction of combination radioimmunotherapy with 5-fluorouracil in colon cancer xenografts. J Cancer Res Clin Oncol 125:630–636PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Ya-Jen Chang
    • 1
  • Chin-Wei Hsu
    • 1
  • Chih-Hsien Chang
    • 1
  • Keng-Li Lan
    • 2
    • 4
  • Gann Ting
    • 3
  • Te-Wei Lee
    • 1
  1. 1.Institute of Nuclear Energy ResearchTaoyuanRepublic of China
  2. 2.Cancer CenterTaipei Veterans General HospitalTaipeiTaiwan
  3. 3.National Health Research InstitutesTaipeiTaiwan
  4. 4.Department of Biomedical Imaging and Radiological SciencesSchool of Biomedical Science and Engineering, National Yang-Ming UniversityTaipeiTaiwan

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