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Cancer Immunology, Immunotherapy

, Volume 56, Issue 1, pp 35–47 | Cite as

Treatment with HPMA copolymer-based doxorubicin conjugate containing human immunoglobulin induces long-lasting systemic anti-tumour immunity in mice

  • Milada SirovaEmail author
  • Jiri Strohalm
  • Vladimir Subr
  • Daniela Plocova
  • Pavel Rossmann
  • Tomas Mrkvan
  • Karel Ulbrich
  • Blanka Rihova
Original Article

Abstract

Linkage of doxorubicin (Dox) to a water-soluble synthetic N-(2-hydroxypropyl)methacrylamide copolymer (PHPMA) eliminates most of the systemic toxicity of the free drug. In EL-4 lymphoma-bearing C57BL/6 mice, a complete regression of pre-established tumours has been achieved upon treatment with Dox–PHPMA–HuIg conjugate. The treatment was effective using a range of regimens and dosages, ranging from 62.5 to 100% cured mice treated with a single dose of 10–20 mg of Dox eq./kg, respectively. Fractionated dosages producing lower levels of the conjugate for a prolonged time period had substantial curative capacity as well. The cured mice developed anti-tumour protection as they rejected subsequently re-transplanted original tumour. The proportion of tumour-protected mice inversely reflected the effectiveness of the primary treatment. The treatment protocol leading to 50% of cured mice produced only protected mice, while no mice treated with early treatment regimen (i.e. starting on day 1 after tumour transplantation) rejected the re-transplanted tumour. Exposure of the host to the cancer cells was a prerequisite for developing protection. The anti-tumour memory was long lasting and specific against the original tumour, as the cured mice did not reject another syngeneic tumour, melanoma B16-F10. The immunity was transferable to naïve recipients in in vivo neutralization assay by spleen cells or CD8+ lymphocytes derived from cured animals. We propose an effective treatment strategy which eradicates tumours without harming the protective immune anti-cancer responses.

Keywords

Targeted tumour therapy HPMA Human immunoglobulin Doxorubicin Complete tumour regression Protective anti-tumour response 

Abbreviations

HPMA

N-(2-hydroxypropyl)methacrylamide

PHPMA

N-(2-hydroxypropyl)methacrylamide copolymer

Dox

Doxorubicin

HuIg

Human intravenous immunoglobulin

IVIg

Intravenous immunoglobulin

NK

Natural killer cells

LAK

Lymphokine-activated killers

LTS

Long-term survivor

MMC

Mitomycin C

Notes

Acknowledgements

The project was supported by the Ministry of Education, Youth and Sports (grant 1M 4635608802), the Czech Science Foundation (grant 305/05/2268), and the Institutional Research Concept AV0Z50200510. We thank Prof. I. Lefkovits for helpful suggestions, and Ms. H. Mišurcová and Ms. H. Semorádová for excellent technical assistance.

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Milada Sirova
    • 1
    Email author
  • Jiri Strohalm
    • 2
  • Vladimir Subr
    • 2
  • Daniela Plocova
    • 2
  • Pavel Rossmann
    • 1
  • Tomas Mrkvan
    • 1
  • Karel Ulbrich
    • 2
  • Blanka Rihova
    • 1
  1. 1.Division of Immunology and Gnotobiology, Institute of MicrobiologyAcademy of Sciences of the Czech RepublicPragueCzech Republic
  2. 2.Department of Biomedicinal Polymers, Institute of Macromolecular ChemistryAcademy of Sciences of the Czech RepublicPragueCzech Republic

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