Treatment with HPMA copolymer-based doxorubicin conjugate containing human immunoglobulin induces long-lasting systemic anti-tumour immunity in mice.
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.
Sirova
Milada
M
Division of Immunology and Gnotobiology, Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic. sirova@biomed.cas.cz
Strohalm
Jiri
J
Subr
Vladimir
V
Plocova
Daniela
D
Rossmann
Pavel
P
Mrkvan
Tomas
T
Ulbrich
Karel
K
Rihova
Blanka
B
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004337:Drug Carriers; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007136:Immunoglobulins / Q000627:therapeutic use*; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D011109:Polymethacrylic Acids / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D015996:Survival Rate; D014407:Tumor Cells, Cultured / Q000637:transplantation
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D007136:Immunoglobulins; D011109:Polymethacrylic Acids; C055176:doxorubicin-N-(2-hydroxypropyl)methacrylamide copolymer conjugate; D004317:Doxorubicin