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Suppression by anticancer agents of reactive oxygen generation from polymorphonuclear leukocytes
Free Radical Research
|January 1, 1996
Summary
Anticancer drugs like 5-FU and CDDP inhibit polymorphonuclear leukocyte (PMN) reactive oxygen generation with long-term use. Short-term use of peplomycin enhances certain signaling pathways but inhibits myeloperoxidase activity.
Area of Science:
- Immunology
- Pharmacology
- Biochemistry
Background:
- Polymorphonuclear leukocytes (PMN) play a crucial role in the immune response, generating reactive oxygen species (ROS) through the respiratory burst.
- Anticancer agents can modulate cellular signaling pathways, potentially impacting immune cell function.
- Understanding the effects of chemotherapy on PMN is vital for managing treatment side effects and optimizing therapeutic outcomes.
Purpose of the Study:
- To investigate the influence of various anticancer agents on signal transduction pathways in PMN related to reactive oxygen generation.
- To elucidate the differential effects of short-term versus long-term exposure to these agents on PMN function.
Main Methods:
- Stimulation of PMN with formyl-methionyl-leucyl-phenylalanine (FMLP) and phorbol myristate acetate (PMA).
- Measurement of inositol 1,4,5-trisphosphate, diacyl glycerol, intracellular calcium ([Ca2+]i) levels, and protein kinase C (PKC) activity.
- Assessment of tyrosine phosphorylation, respiratory burst, and chemiluminescence.
- Treatment with cis-diammine-dichloroplatinum (CDDP), 5-fluorouracil (5-FU), 137Cs, peplomycin (PLM), and genistein.
Main Results:
- CDDP, 5-FU, 137Cs, and PLM decreased inositol trisphosphate and diacyl glycerol levels in FMLP-stimulated PMN.
- 5-FU and CDDP reduced [Ca2+]i and PKC activity post-PMA stimulation, while PLM increased them.
- Long-term treatment (8h) with 5-FU, CDDP, and radiation suppressed ROS generation, whereas short-term (<4h) treatment with PLM, 5-FU, and CDDP enhanced it.
- PLM enhanced PKC translocation and tyrosine kinase activation but inhibited myeloperoxidase (MPO) activity.
Conclusions:
- Long-term treatment with 5-FU and CDDP inhibits PMN respiratory burst by suppressing calcium mobilization, PKC translocation, and tyrosine kinase activation.
- Short-term peplomycin treatment enhances PKC and tyrosine kinase activation but inhibits MPO activity.
- Radiation exhibits a weak inhibitory effect on signal transduction for PMN respiratory burst.