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Efficacy and selectivity of monoclonal‐antibody‐targeted drugs and free methotrexate in fluorescence‐labelled mixed tumour‐cell monolayer cultures and multicellular spheroids
Author(s) -
Embleton M. J.,
Charleston Angela,
Affleck Karen
Publication year - 1991
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.2910490416
Subject(s) - cytotoxicity , cytotoxic t cell , monoclonal antibody , cell culture , chemistry , cell , microbiology and biotechnology , conjugate , spheroid , antibody , biology , in vitro , biochemistry , immunology , mathematical analysis , genetics , mathematics
Free methotrexate (MTX) and 2 monoclonal antibody (MAb)‐MTX conjugates were tested against mixed human tumour‐cell cultures, in which 2 cell lines of differing antigenicity or drug sensitivity, pre‐labelled with fluorescent dyes, were added together in microtitre wells. Conjugates were selectively cytotoxic for cells bearing high concentrations of the relevant antigen, and MTX was preferentially cytotoxic for wild‐type cells rather than MTX‐resistant variants when tested on separate cultures. In mixed cultures these selectivities were substantially retained, although there was a varying tendency towards intermediate cytotoxicity for each cell line of the pair. MTX was cytotoxic for cell line 791T grown as multicellular spheroids, but MAb‐MTX conjugate and a MAb‐RTA immunotoxin showed little cytotoxicity against spheroids at the highest concentrations tested, although they were highly effective against monolayer cells. Mixed spheroids could be formed efficiently from most cell lines, although in some cases cell distribution was non‐random. In mixed spheroids prepared between wild‐type and MTX‐resistant 791T variants, relative MTX sensitivities conformed broadly to those seen in separate monolayer cultures. Fluorescence‐labelling was a reliable method for determining cell behaviour under the above conditions. We conclude that selectivity of therapeutic agents in mixed cultures was partially, but not completely, impaired compared to that observed in separate cultures, and (b) that low M r drugs are effective against 3‐dimensional tumour‐cell structures but antibody‐targeted conjugates are not.