Effects of antibodies induced by a conjugate vaccine on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone absorptive transport, metabolism, and proliferation of human lung cells.
One of the most abundant and potent lung carcinogen is the nicotine-derived tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The monoclonal antibody P9D5 induced with a NNK-conjugate vaccine was used to investigate the ability of NNK-specific antibodies to modulate NNK-induced adverse effects as well as its absorptive transport and metabolism in two lung cancer cell lines (Calu-3 and NCI-H82). Transport experiments in Calu-3 cells with a 50-fold molar excess of apical P9D5 increased the recovery of coadministered apical NNK, with a concomitant decrease in NNK transepithelial transport of more than 50% compared to controls. In contrast, basolateral P9D5 did neither influence transepithelial transport of NNK nor its disappearance from the apical compartment. Calu-3 cells were also found to reduce NNK to NNAL and a 65-fold molar excess of NNK-specific antibody inhibited this metabolic conversion by 46 and 54% compared to irrelevant control antibody after 48 and 72 hr, respectively. The biological relevance of NNK redistribution by antibody was demonstrated by reversion of NNK-induced cell proliferation in NCI-H82 cells. Repartitioning of tobacco carcinogens by antibody may reduce their early effective peak concentrations in susceptible target organs and thus relieve overloaded local DNA repair mechanisms and diminish carcinogen-induced cell proliferation. These in vitro data therefore suggest that a prophylactic antibody response may be associated with a reduced risk of cancer.
De Buck
Stefan S
SS
Institute of Immunology, LNS/CRP-Santé, Luxembourg, Grand Duchy of Luxembourg.
Schellenberger
Mario T
MT
Ensch
Corinne
C
Muller
Claude P
CP
D000911:Antibodies, Monoclonal / Q000276:immunology*; D001692:Biological Transport; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008168:Lung / Q000166:cytology / Q000276:immunology*; D008175:Lung Neoplasms / Q000473:pathology*; D009602:Nitrosamines / Q000276:immunology* / Q000378:metabolism / Q000493:pharmacokinetics; D014612:Vaccines / Q000276:immunology*
D000911:Antibodies, Monoclonal; D009602:Nitrosamines; D014612:Vaccines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone