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.

• MeSH
• doxorubicin analogy a deriváty   terapeutické užití   MeSH
• imunoglobuliny terapeutické užití   MeSH
• imunologická tolerance * MeSH
• kyseliny polymethakrylové terapeutické užití   MeSH
• lidé MeSH
• lymfom T-buněčný farmakoterapie   imunologie   prevence a kontrola   MeSH
• melanom experimentální farmakoterapie   imunologie   metabolismus   MeSH
• míra přežití MeSH
• myši inbrední C57BL MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buňky kultivované transplantace   MeSH
• nádory kůže farmakoterapie   imunologie   metabolismus   MeSH
• nosiče léků MeSH
• protinádorová antibiotika terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• doxorubicin-N-(2-hydroxypropyl)methacrylamide copolymer conjugate MeSH Prohlížeč
• doxorubicin MeSH
• imunoglobuliny MeSH
• kyseliny polymethakrylové MeSH
• nosiče léků MeSH
• protinádorová antibiotika MeSH

PURPOSE: Two different monoclonal antibody-targeted HPMA copolymer-doxorubicin conjugates, classic and starlike, were synthesized to be used for site-specific cancer therapy. The anti-mouse Thy-1.2 (IgG3) and two anti-human CD71/A (IgG1) and CD71/B (IgG2a) monoclonal antibodies were used as targeting structures. METHODS: Their binding and cytotoxic activity in vitro, body distribution, and anticancer activity in vivo were evaluated. RESULTS: The results of flow cytometric analysis showed comparable binding of classic and starlike conjugates to the target cells. The in vitro cytotoxic effect was 10-fold higher if cancer cells were exposed to the starlike conjugate compared to the classic one. Biodistribution studies showed that the starlike conjugate remained in a relatively high concentration in blood, whereas the classic conjugate was found in a 6.5-times lower amount. In contrast to the low antitumor activity of free doxorubicin and nontargeted HPMA copolymer-doxorubicin conjugate, both anti-Thy-1.2 targeted conjugates (classic and starlike) cured all mice bearing T-cell lymphoma EL4. On the other hand, starlike conjugates containing anti-CD71/A or anti-CD71/B monoclonals as targeting structures were more effective against human colorectal cancer SW 620 than the classic one. CONCLUSIONS: We have shown that the starlike conjugates are more effective systems for targeted drug delivery and cancer treatment than classic conjugates.

• MeSH
• buněčné dělení účinky léků   MeSH
• doxorubicin chemie   farmakokinetika   farmakologie   MeSH
• kolorektální nádory farmakoterapie   MeSH
• lidé MeSH
• lymfom T-buněčný farmakoterapie   MeSH
• methakryláty chemie   farmakologie   MeSH
• molekulární struktura MeSH
• monoklonální protilátky chemie   metabolismus   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• prekurzory léčiv chemie   farmakologie   MeSH
• protinádorová antibiotika chemie   farmakokinetika   farmakologie   MeSH
• techniky in vitro MeSH
• tkáňová distribuce MeSH
• transplantace nádorů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• doxorubicin MeSH
• hydroxypropyl methacrylate MeSH Prohlížeč
• methakryláty MeSH
• monoklonální protilátky MeSH
• prekurzory léčiv MeSH
• protinádorová antibiotika MeSH