Suppression by anticancer agents of reactive oxygen generation from polymorphonuclear leukocytes.

Abstract

The influence of anticancer agents on signal transduction for reactive oxygen generation was examined in polymorphonuclear leukocytes (PMN). Inositol 1,4,5-trisphosphate and diacyl glycerol levels in formyl-methionyl-leucyl-phenylalanine (FMLP)-stimulated PMN were decreased by cis-diammine-dichloroplatinum (CDDP), 5-fluorouracil (5-FU), 137Cs, and peplomycin (PLM, a bleomycin analog) in this order. Intracellular calcium ([Ca2+]i) level and protein kinase C (PKC) activity in the membrane after phorbol myristate acetate (PMA) stimulation were decreased by 5-FU and CDDP but not by 137Cs and, in contrast, were increased by PLM. The level of [Ca2+]i was decreased by 8 h treatment with 5-FU and CDDP. 5-FU and CDDP inhibited tyrosine phosphorylation of 83-kDa and 115-kDa proteins, however 137Cs did not inhibit their phosphorylation and PLM enhanced the tyrosine phosphorylation. Short term (< or = 4 h) treatment with PLM, 5-FU and CDDP enhanced respiratory burst of PMN, whereas long term (8 h) treatment, as well as radiation, suppressed reactive oxygen generation from PMN in a dose dependent manner. Genistein suppressed chemiluminescence in 5-FU-, CDDP-, and 137Cs-pretreated PMN to a greater extent than it did in PLM-pretreated PMN, however near suppression of chemiluminescence by staurosporine, 4-bromophenyl bromide and methionine was observed in PMN pretreated with these agents. In conclusion, these results indicate that long term treatment of PMN with 5-FU and CDDP inhibit respiratory burst, suppressing intracellular calcium mobilization, PKC translocation and tyrosine kinase activation, in adverse, short term treatment with PLM enhances PKC translocation and tyrosine kinase activation, but inhibits myeloperoxidase (MPO) activity, and radiation causes weak inhibition of signal transduction for respiratory burst.