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

Abstract

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 . 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.Overwhelming epidemiological and biological evidence exposes tobacco smoking as the main cause of the dramatic increase in lung cancer worldwide during the 20th century.

Cloning and Characterization of a Hybridoma Secreting a 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-Specific Monoclonal Antibody and Recombinant F(ab)

“…Previous studies using monoclonal antibodies have mitigated the acute toxicity effects of drugs such as cocaine, heroin, methamphetamine, colchicine, oleander and other related substances [37,38,39,40]. Others have ameliorated the chronic toxicity associated with chemicals such as PCP, NNK and nicotine [17,41,42,43]. The current work builds upon these studies by creating a high affinity recombinant anti-NNK binding site derived from a mouse monoclonal antibody specific for NNK.…”

Evaluation of adjuvants for a candidate conjugate vaccine against benzo[a]pyrene

“…26 Our earlier work demonstrated that antibodies derived against low molecular weight carcinogens protect cells in vitro by a number of expected and unexpected mechanisms against adverse effects of carcinogens. 12,[23][24][25] We demonstrated in a bicompartment model of polarized intestinal cells (Caco-2) that antibodies have the potential to reduce the absorptive transport. 23 The biological relevance of antibodies was shown by modulating the B[a]P metabolism and DNA adduct formation in vitro.…”

“…12,13 Hapten-specific antibodies against biologically active low molecular weight compounds have been widely applied as therapeutic agents to reverse their pharmacological effects, [14][15][16][17][18][19][20][21][22] but their use as immunoprophylactic agents has only recently gained some interest. 12,[23][24][25][26][27][28][29] Several candidate vaccines against nicotine and cotinine, its major metabolite, have been developed and are in clinical trials. 14,22,[30][31][32][33] We have developed an experimental vaccine based on B[a]P conjugated to tetanus toxoid (TT) or diphtheria toxoid (DT) as carrier proteins, that induces high levels of antibodies against this carcinogen.…”

Immunomodulation of carcinogens-induced steroids-dependent human diseases

“…Mucosal Abs inhibited the transport of Cg into and through respiratory and intestinal epithelium in vivo (Moolten et al, 1978a, Silbart and Keren, 1989, Rasmussen and Silbart, 1998), as well as mucosal-like monoclonal Abs in the model experiments in vitro with dialysis membrane (Silbart et al, 1996) or epithelium cell monolayers (De Buck et al, 2005, De Buck et al, 2010). The monoclonal mucosal-like Abs reduced the amount of Cg genotoxic metabolites and inhibited the Cg-induced cells proliferation in vitro (De Buck et al, 2005, De Buck et al, 2010). In contrast serum-like model Abs increased the penetration of Cg through membrane or cell monolayers and its metabolic activation (Silbart et al, 1996, De Buck et al, 2005).…”