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Ann Thorac Surg 1996;62:1459
© 1996 The Society of Thoracic Surgeons
DR LARRY R. KAISER (Philadelphia, PA): I thank The Society for giving me the privilege of discussing this report, and I congratulate Dr Snider and associates on this preliminary work. Unfortunately, they did not provide me with a copy of their manuscript, so my comments are, per force, based only on the abstract.
Targeted antineoplastic therapy that is specific for tumor cells and nontoxic to normal cells is indeed the goal in the treatment of malignant disease. Currently no such therapy exists. Any benefit derived from therapy unfortunately carries a price. Antibody conjugate therapies, like the one you have heard about today, are designed for systemic use, and therefore one needs a truly specific target for these therapies to be efficacious. I have several questions for Dr Snider. What is the expression of c-erbB-2 in normal cells, specifically endothelial cells? Have you tried your antibody conjugate on any cells with lower levels of expression of c-erbB-2? Even though, as you mention, up to one third of non–small cell lung cancers may produce c-erbB-2, or may express it, heterogeneity within a tumor may render most tumors relatively nonsensitive, because there may be a significant population of cells with low-level expression. Have you looked at the heterogeneity of expression within tumors?
One of the problems with murine monoclonal antibodies is inability to repeatedly challenge humans due to the development of sensitization to the mouse protein. What about the problem of repeated challenges, or do you anticipate that one treatment will be effective? You incubated the cells for 7 days. Did you try a shorter exposure of cells to the antibody conjugate? It is difficult to envision in vivo saturation of cells for 7 days.
Seemingly, monoclonal antibodies have difficulty penetrating tumor masses and cannot hope to reach all cells. In your model did you note any rebound growth? And, finally, was the effect you observed cytotoxic or really only cytostatic?
DR SNIDER: Thank you, Dr Kaiser, for your remarks.
Normal tissue expression of c-erbB-2–encoded p185 is usually about 1 million times less than that in tumors that overexpress this antigen. The heterogeneity of oncogene overexpression was not examined in the current study.
Previous clinical trials of cytotoxic immunoconjugate therapy have revealed the existence of limiting side effects, which may be linked to repeated challenges with immune therapy developed in a nonhuman source. The conjugate whose tumor-specific effects we report on today is serving only as first-generation probe to determine whether c-erbB-2/p185 is a suitable target for immune-based therapy. The goal would be to modify a similar immunoconjugate, such that only the antigen-specific portion of the antibody and the active segment of the toxin could be linked and administered to minimize potential side effects and maximize potency.
An incubation period of 5 to 7 days was necessary to allow the untreated control cells to reach 50% to 75% confluence, thereby ensuring log-phase growth. The 4D5-gelonin conjugate had a cytotoxic rather than a cytostatic effect, as direct observation and crystal violet assay staining revealed only cellular debris in treated cultures.
Related Article
Ann. Thorac. Surg. 1996 62: 1454-1459.
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