Abstract
We provide data on in vivo targeting of the Thy 1.2 (CDw90) cell surface
receptor expressed on neoplastic T cells, mouse EL4 T cell lymphoma.
The targeting antibody and the anticancer drug, doxorubicin (DOX)
were conjugated to a water-soluble copolymer based on N-(2-hydroxypropyl)methacrylamide
(HPMA) acting as a carrier responsible for controlled intracellular
release of the conjugated drug. The in vivo therapeutic efficacy
of HPMA copolymer-bound DOX targeted with anti-EL4 antibody, polyclonal
anti-thymocyte globulin (ATG), monoclonal anti-Thy 1.2 antibody or
its F(ab')(2) fragment was compared with the efficacy of DOX conjugated
to HPMA copolymer containing nonspecific IgG or bovine serum albumin
(BSA). Anti-EL4 antibody-targeted conjugate caused a significant
retardation of tumor growth and an extension of the life span of
treated mice. The effect was comparable with that of HPMA copolymer-bound
DOX targeted with ATG, anti-Thy 1.2 antibody or its F(ab')(2) fragment.
However, considerable antitumor effect was seen also in conjugates
targeted instead of specific antibodies with syngeneic nonspecific
IgG or BSA. Patients with advanced cancer are often immunocompromised
due to dysfunction of their immune system induced by cancer and cytotoxic
drugs. A significant decrease of unwanted side-effects of targeted
drugs against a number of vital organs was already documented. In
this study we have compared immunotoxic effects of free DOX with
those of its antibody-targeted form on NK cells and cytolytic T lymphocytes
(CTLs) isolated from C57BL/10 mice bearing EL4 T cell lymphoma. In
the same model we have tested the combination therapy with immunomodulators
(beta-glucan or AM-2) injected together with targeted daunomycin.
We have observed a significant protective effect of targeted DOX
against NK cells and CTLs. Moreover, the data revealed that combination
therapy considerably enhances antitumor efficacy of the targeted
anticancer drug.
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