title: Failure of neutrophil chemotactic function in breast cancer patients treated with chemotherapy.
abstract: Neutrophil migration is a key host event against infection. Chemotherapy may alter neutrophil function and favor increased risk of infection. Herein, we investigated the effect of chemotherapy on the migration capacity of circulating neutrophils obtained from breast cancer patients and mechanisms involved in this event. Breast cancer women (n=23) at disease stage I-III and healthy control women (n=25) were prospectively enrolled. No differences in the in vitro migratory responses towards the chemotactic stimuli N-formyl- L-methionyl- L-leucyl- L-phenylalanine (fMLP), leukotriene B(4) (LTB(4)) and interleukin (IL)-8 were observed in purified neutrophils from controls and patients, in a microchemotaxis chamber assay. However, the migration capacity evaluated upon chemotherapy (5-fluoruracil, adriamycin and cyclophosphamide, 21-day intervals between cycles, total leukocyte count >/=2,000/mm(3)), on the day immediately before the beginning of the sixth cycle, showed that patient neutrophils (n=14) failed to migrate in response to fMLP compared to response observed upon diagnosis. Considering patients (n=8) with documented bacterial infection between cycles, the number of migrated neutrophils (mean+/-SD) compared to response at diagnosis was markedly reduced upon chemotherapy to either fMLP (30.1+/-8.26 vs. 2.81+/-1.28) or LTB(4) (15.72+/-4.8 vs. 2.8+/-1.64) stimuli respectively. Treatment of control neutrophils with sera of chemotherapy-treated patients with infective episodes, to test for the presence of circulating immunosuppressive factors, significantly reduced the migratory capacity of healthy neutrophils to fMLP, LTB(4) and IL-8, in a dose-dependent way. But no significant differences were found in the serum levels of nitric oxide (NO) metabolites, tumor necrosis factor (TNF)-alpha, IL-6, IL-8 and IL-10 collected at the same time as the collection of blood for neutrophil migration experiments. In conclusion, breast cancer patients showed suppressed neutrophil migratory response upon chemotherapy, accompanied by bacterial infection episodes. Circulating factors are involved, at least partially, in the inhibitory mechanism on neutrophil migration.
authors.affiliation: Department of Biological Sciences, Faculty of Medicine of Triângulo Mineiro, Praça Manoel Terra, 330, CEP, 38015-050, Uberaba-MG, Brazil.
authors.forename: Maria Angélica O
authors.initials: MA
authors.lastname: Mendonça
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Eddie Fernando C
authors.initials: EF
authors.lastname: Murta
authors.forename: Beatriz M
authors.initials: BM
authors.lastname: Tavares-Murta
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy*; D016022:Case-Control Studies; D002465:Cell Movement; D002634:Chemotaxis, Leukocyte; D003520:Cyclophosphamide; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood / Q000494:pharmacology; D007958:Leukocyte Count; D007975:Leukotriene B4 / Q000494:pharmacology; D008875:Middle Aged; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D020360:Neoadjuvant Therapy; D009504:Neutrophils / Q000502:physiology*; D009569:Nitric Oxide / Q000008:administration & dosage / Q000378:metabolism; D011446:Prospective Studies; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007975:Leukotriene B4; D009569:Nitric Oxide; D009240:N-Formylmethionine Leucyl-Phenylalanine; D004317:Doxorubicin; D003520:Cyclophosphamide; D005472:Fluorouracil