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Conjugates of elliptinium acetate with mouse monoclonal anti‐α‐fetoprotein antibodies or fab fragments: In vitro cytotoxic effects upon human hepatoma cell lines
Author(s) -
Alberici Gilles F.,
Pallardy Marc,
Manil Luc,
Dessaux JeanJacques,
Fournier Jacqueline,
Mondesir JeanMarc,
Bohuon Claude,
Gros Pierre
Publication year - 1988
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910410224
Subject(s) - conjugate , chemistry , monoclonal antibody , doxorubicin , in vitro , cytotoxic t cell , microbiology and biotechnology , cytotoxicity , antibody , cell culture , biochemistry , biology , immunology , chemotherapy , mathematical analysis , genetics , mathematics
Elliptinium acetate (EA) is a new anti‐cancer compound displaying cytostatic activity against various malignancies including hepatoma. Using 3 hepatoma cell lines, we compared the in vitro activity of doxorubicin (reference drug), of EA and of conjugates made up with this latter drug and monoclonal antibodies (MAbs). The linkage was performed by a direct oxidation method. Specific immunoconjugates were prepared with an anti‐alphafetoprotein (AFP) MAb (AF01) or its Fab fragment (Fab AF01). Non‐specific conjugates were obtained with an anti‐thyroglobulin MAb (TG01) or its Fab (Fab TG01). Direct membrane injury ( 51 Cr‐release), DNA and protein synthesis as well as AFP release were investigated for all compounds. Free EA displayed only weak activity on DNA and protein synthesis, at 10‐fold higher molar concentration than doxorubicin. Conjugation of EA with whole AF01 allowed significant potentiation of protein synthesis inhibition without affecting the 3 other tests. In contrast, Fab AF01 × EA conjugates displayed a marked effect in the 4 tests; in particular, this conjugate was at least 100 times more efficient than any other compound when tested in the 51 Cr‐release test. Neither Fab AF01 nor free EA alone or in combination exhibited such an effect. Fab TG01 × EA conjugate was not directly cytotoxic but potentiated inhibition of DNA and protein synthesis between 2‐ and 10‐fold. The mechanism of the direct cytotoxic effect of anti‐AFP Fab × EA conjugate, which has never been described in any other immunodrug model, was investigated.