Skip to main content

Advertisement

SpringerLink
Log in

Local Delivery of Interleukin-2 and Adriamycin is Synergistic in the Treatment of Experimental Malignant Glioma

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Summary

Introduction: Local delivery of adriamycin (ADR) via biodegradable polymers has been shown to improve survival in rats challenged intracranially with 9L gliosarcoma. Likewise, local delivery of interleukin-2 (IL-2) has been shown to extend survival in experimental brain tumor models. In the current study, we hypothesized that local delivery of ADR and IL-2 might act synergistically against experimental intracranial glioma.

Methods: Polyanhydride polymers (PCPP-SA) containing 5% ADR by weight were prepared using the mix-melt method. IL-2 polymer microspheres (IL-2 MS) were produced via the complex coacervation of gelatin and chondroitin sulfate in the presence of IL-2. Sixty male Fisher 344 rats received an intracranial challenge with a lethal dose of 9L gliosarcoma cells. In addition, a group of rats were injected with either IL-2 MS or empty microspheres. Five days later they received ADR or blank polymer. There were a total of four treatment groups: (1) empty microspheres, blank polymer; (2) empty microspheres, ADR polymer; (3) IL-2 MS, blank polymer; and (4) IL-2 MS, ADR polymer.

Results: Compared to control animals treated with empty microspheres and blank polymer, animals receiving empty microspheres and ADR polymer (P < 0.0004), IL-2 MS and blank polymer (P < 0.0005), and IL-2 MS combined with ADR polymer (P < 0.0000002) all showed statistically significant improvement in survival. In addition, animals receiving the IL-2/ADR combination had significantly extended survival compared to either ADR or IL-2 alone (P < 0.000003 and P < 0.0004, respectively).

Conclusions: Both ADR and IL-2, when delivered locally, are effective monotherapeutic agents against experimental intracranial gliosarcoma. The combination ADR and IL-2 therapy is more effective than either agent alone.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. H Brem et al. (1991) ArticleTitleInterstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas J Neurosurg 74 441–446 Occurrence Handle1993909

    PubMed  Google Scholar 

  2. H Brem et al. (1995) ArticleTitlePlacebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group Lancet 345 1008–1012 Occurrence Handle10.1016/S0140-6736(95)90755-6 Occurrence Handle7723496

    Article  PubMed  Google Scholar 

  3. S Valtonen et al. (1997) ArticleTitleInterstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study Neurosurgery 41 44–48 Occurrence Handle10.1097/00006123-199707000-00011 Occurrence Handle9218294

    Article  PubMed  Google Scholar 

  4. KA Walter RJ Tamargo A Olivi PC Burger H Brem (1995) ArticleTitleIntratumoral chemotherapy Neurosurgery 37 1128–1145 Occurrence Handle8584154

    PubMed  Google Scholar 

  5. M Westphal et al. (2003) ArticleTitleA phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma Neuro-oncol 5 79–88 Occurrence Handle10.1215/S1522851702000236 Occurrence Handle12672279

    Article  PubMed  Google Scholar 

  6. JE Wolff T Trilling G Molenkamp RM Egeler H Jurgens (1999) ArticleTitleChemosensitivity of glioma cells in vitro: a meta analysis J Cancer Res Clin Oncol 125 481–486 Occurrence Handle10.1007/s004320050305 Occurrence Handle10480340

    Article  PubMed  Google Scholar 

  7. T. Ohnishi et al. (1995) ArticleTitleIn vivo and in vitro evidence for ATP-dependency of P-glycoprotein-mediated efflux of doxorubicin at the blood-brain barrier Biochem Pharmacol 49 1541–1544 Occurrence Handle10.1016/0006-2952(95)00082-B Occurrence Handle7763297

    Article  PubMed  Google Scholar 

  8. RJ Tushinksi (1991) Biology of cytokines: the interleukins VT Devita S Hellman SA Rosenberg (Eds) Biologic Therapy of Cancer J.B. Lippincott Company Philadelphia 87–94

    Google Scholar 

  9. DM Pardoll (1995) ArticleTitleParacrine cytokine adjuvants in cancer immunotherapy Annu Rev Immunol 13 399–415 Occurrence Handle10.1146/annurev.iy.13.040195.002151 Occurrence Handle7612229

    Article  PubMed  Google Scholar 

  10. ER Fearon et al. (1990) ArticleTitleInterleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response Cell 60 397–403 Occurrence Handle10.1016/0092-8674(90)90591-2 Occurrence Handle2137372

    Article  PubMed  Google Scholar 

  11. SA Rosenberg et al. (1989) ArticleTitleExperience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients Ann Surg 210 474–484 Occurrence Handle2679456

    PubMed  Google Scholar 

  12. T Lichtor RP Glick TS Kim R Hand EP Cohen (1995) ArticleTitleProlonged survival of mice with glioma injected intracerebrally with double cytokine-secreting cells J Neurosurg 83 1038–1044 Occurrence Handle7490618

    PubMed  Google Scholar 

  13. RC Thompson et al. (1996) ArticleTitleSystemic and local paracrine cytokine therapies using transduced tumor cells are synergistic in treating intracranial tumors J Immunother Emphasis Tumor Immunol 19 405–413 Occurrence Handle9041459

    PubMed  Google Scholar 

  14. RP Glick T Lichtor E Zoeten Particlede P Deshmukh EP Cohen (1999) ArticleTitleProlongation of survival of mice with glioma treated with semiallogeneic fibroblasts secreting interleukin-2 Neurosurgery 45 867–874 Occurrence Handle10.1097/00006123-199910000-00028 Occurrence Handle10515482

    Article  PubMed  Google Scholar 

  15. T Lichtor et al. (2002) ArticleTitleApplication of interleukin-2-secreting syngeneic/allogeneic fibroblasts in the treatment of primary and metastatic brain tumors Cancer Gene Ther 9 464–469 Occurrence Handle10.1038/sj.cgt.7700459 Occurrence Handle11961669

    Article  PubMed  Google Scholar 

  16. J Hanes et al. (2001) ArticleTitleControlled local delivery of interleukin-2 by biodegradable polymers protects animals from experimental brain tumors and liver tumors Pharm Res 18 899–906 Occurrence Handle10.1023/A:1010963307097 Occurrence Handle11496947

    Article  PubMed  Google Scholar 

  17. A Nigam et al. (1998) ArticleTitleImmunomodulatory properties of antineoplastic drugs administered in conjunction with GM-CSF-secreting cancer cell vaccines Int J Oncol 12 161–170 Occurrence Handle9454900

    PubMed  Google Scholar 

  18. K Tsung JB Meko YL Tsung GR Peplinski JA Norton (1998) ArticleTitleImmune response against large tumors eradicated by treatment with cyclophosphamide and IL-12 J Immunol 160 1369–1377 Occurrence Handle9570556

    PubMed  Google Scholar 

  19. P Sampath et al. (1999) ArticleTitleParacrine immunotherapy with interleukin-2 and local chemotherapy is synergistic in the treatment of experimental brain tumors Cancer Res 59 2107–2114 Occurrence Handle10232596

    PubMed  Google Scholar 

  20. LD Rhines et al. (2003) ArticleTitleLocal immunotherapy with interleukin-2 delivered from biodegradable polymer microspheres combined with interstitial chemotherapy: a novel treatment for experimental malignant glioma Neurosurgery 52 872–879 Occurrence Handle10.1227/01.NEU.0000053211.39087.D1 Occurrence Handle12657184

    Article  PubMed  Google Scholar 

  21. EP Sipos B Tyler S Piantadosi PC Burger H Brem (1997) ArticleTitleOptimizing interstitial delivery of BCNU from controlled release polymers for the treatment of brain tumors Cancer Chemother Pharmacol 39 383–389 Occurrence Handle10.1007/s002800050588 Occurrence Handle9054951

    Article  PubMed  Google Scholar 

  22. A Olivi et al. (1996) ArticleTitleInterstitial delivery of carboplatin via biodegradable polymers is effective against experimental glioma in the rat Cancer Chemother Pharmacol 39 90–96

    Google Scholar 

  23. E Kaplan P Meier (1958) ArticleTitleNon-parametric estimation from incomplete observations J Am Stat Associ 53 457–481

    Google Scholar 

  24. N Mantel W Haenszel (1959) ArticleTitleStatistical aspects of the analysis of data from retrospective studies of disease J Natl Cancer Inst 22 719–748 Occurrence Handle13655060

    PubMed  Google Scholar 

  25. P Hau et al. (2004) ArticleTitlePegylated liposomal doxorubicin-efficacy in patients with recurrent high-grade glioma Cancer 100 1199–1207 Occurrence Handle10.1002/cncr.20073 Occurrence Handle15022287

    Article  PubMed  Google Scholar 

  26. SC Steiniger et al. (2004) ArticleTitleChemotherapy of glioblastoma in rats using doxorubicin-loaded nanoparticles Int J Cancer 109 759–767 Occurrence Handle10.1002/ijc.20048 Occurrence Handle14999786

    Article  PubMed  Google Scholar 

  27. M Rittierodt K Harada (2003) ArticleTitleRepetitive doxorubicin treatment of glioblastoma enhances the PGP expression – a special role for endothelial cells Exp Toxicol Pathol 55 39–44 Occurrence Handle10.1078/0940-2993-00287 Occurrence Handle12940627

    Article  PubMed  Google Scholar 

  28. RP Glick T Lichtor TS Kim S Ilangovan EP Cohen (1995) ArticleTitleFibroblasts genetically engineered to secrete cytokines suppress tumor growth and induce antitumor immunity to a murine glioma in vivo Neurosurgery 36 548–555 Occurrence Handle7753355

    PubMed  Google Scholar 

  29. W Griffitt RP Glick T Lichtor EP Cohen (1998) ArticleTitleSurvival and toxicity of an allogeneic cytokine-secreting fibroblast vaccine in the central nervous system Neurosurgery 42 335–340 Occurrence Handle10.1097/00006123-199802000-00075 Occurrence Handle9482184

    Article  PubMed  Google Scholar 

  30. L Staib W Harel MS Mitchell (1993) ArticleTitleProtection against experimental cerebral metastases of murine melanoma B16 by active immunization Cancer Res 53 1113–1121 Occurrence Handle8439956

    PubMed  Google Scholar 

  31. WF Hickey (1991) ArticleTitleMigration of hematogenous cells through the blood-brain barrier and the initiation of CNS inflammation Brain Pathol 1 97–105 Occurrence Handle1669702

    PubMed  Google Scholar 

  32. A Fontana H Hengartner N Tribolet Particlede E Weber (1984) ArticleTitleGlioblastoma cells release interleukin 1 and factors inhibiting interleukin 2-mediated effects J Immunol 132 1837–1844 Occurrence Handle6607949

    PubMed  Google Scholar 

  33. SC Saris et al. (1992) ArticleTitleTreatment of murine primary brain tumors with␣systemic interleukin-2 and tumor-infiltrating lymphocytes J Neurosurg 76 513–519 Occurrence Handle1738033

    PubMed  Google Scholar 

  34. A Akbasak EH Oldfield SC Saris (1991) ArticleTitleExpression and modulation of major histocompatibility antigens on murine primary brain tumor in vitro J Neurosurg 75 922–992 Occurrence Handle1941122

    PubMed  Google Scholar 

  35. F DiMeco et al. (2000) ArticleTitleParacrine delivery of IL-12 against intracranial 9L gliosarcoma in rats J Neurosurg 92 419–427 Occurrence Handle10701528

    PubMed  Google Scholar 

  36. CE Weber (1998) ArticleTitleCytokine-modified tumor vaccines: an antitumor strategy revisited in the age of molecular medicine Cancer Nurs 21 167–177 Occurrence Handle10.1097/00002820-199806000-00003 Occurrence Handle9615507

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Neurosurgery and Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD

    Wesley Hsu, Betty Tyler & Henry Brem

  2. Division of Neurosurgery, The university of Chicago, 5841 South Maryland Avenue, MC 3026, Chicago, Illinois, 60637, IL, USA

    Maciej S. Lesniak

Authors
  1. Wesley Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maciej S. Lesniak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Betty Tyler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Henry Brem
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maciej S. Lesniak.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hsu, W., Lesniak, M.S., Tyler, B. et al. Local Delivery of Interleukin-2 and Adriamycin is Synergistic in the Treatment of Experimental Malignant Glioma. J Neurooncol 74, 135–140 (2005). https://doi.org/10.1007/s11060-004-6597-8

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-004-6597-8

Keywords

Search

Navigation