Effect of anticancer drugs on macrophage-mediated antibody-dependent cytotoxicity and secretion of reactive oxygen intermediates
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1Department of Physiology, Albany Medical College, NY 12208.
Abstract:
The in vitro effects of methotrexate, vincristine, dexamethasone and adriamycin to modulate the antibody dependent cellular cytotoxicity (ADCC) reaction and secretion of superoxide (O2-) and hydrogen peroxide (H2O2) by phorbol myristate acetate (PMA) stimulated rat peritoneal macrophages were studied. Macrophage-mediated ADCC, as measured by the lysis of 51Cr-labeled IgG-coated sheep red blood cells in an 18 h assay, was significantly enhanced in the presence of 100 ng/ml of PMA. Treatment of macrophage monolayers for 24 h with vincristine (10(-5)-10(-7) M), dexamethasone (10(-5)-10(-9) M) and adriamycin (10(-6) M) inhibited ADCC by PMA stimulated macrophages. Vincristine, dexamethasone and adriamycin also inhibited the secretion of O2- and H2O2 by PMA stimulated macrophages at similar concentrations that reduced the ADCC reaction. Methotrexate (10(-3)-10(-7) M) did not inhibit either ADCC or O2- and H2O2 secretion by PMA stimulated macrophages. These results suggest that select anticancer drugs can inhibit macrophage mediated cytotoxicity of antibody coated target cells by suppressing the release of reactive oxygen intermediates by activated macrophages.
Insights
Certain anticancer drugs, including vincristine, dexamethasone, and adriamycin, suppress antibody-dependent cellular cytotoxicity (ADCC) in macrophages. These drugs inhibit the release of reactive oxygen species, impacting macrophage-mediated cancer cell killing.
Area of Science:
- Immunology
- Pharmacology
Background:
- Antibody-dependent cellular cytotoxicity (ADCC) is a key mechanism of macrophage-mediated immunity.
- Reactive oxygen species (ROS), such as superoxide (O2-) and hydrogen peroxide (H2O2), are involved in cellular functions, including cytotoxicity.
Purpose of the Study:
- To investigate the in vitro effects of select anticancer drugs on ADCC and ROS secretion by activated rat peritoneal macrophages.
- To determine if anticancer drugs modulate macrophage-mediated cytotoxicity.
Main Methods:
- Rat peritoneal macrophages were stimulated with phorbol myristate acetate (PMA).
- ADCC was measured using 51Cr-labeled sheep red blood cells.
- Superoxide and hydrogen peroxide secretion were quantified.
- Macrophages were treated with methotrexate, vincristine, dexamethasone, and adriamycin.
Main Results:
- PMA significantly enhanced macrophage-mediated ADCC.
- Vincristine, dexamethasone, and adriamycin inhibited ADCC and ROS secretion in a dose-dependent manner.
- Methotrexate did not affect ADCC or ROS secretion at the tested concentrations.
Conclusions:
- Vincristine, dexamethasone, and adriamycin can suppress macrophage-mediated ADCC.
- Inhibition of ADCC by these drugs may be linked to reduced reactive oxygen intermediate release.
- These findings highlight potential immunomodulatory effects of certain anticancer agents.