The anti-endotoxin agent, rBPI21, significantly attenuates surgically induced tumour growth in an experimental metatases murine model of breast cancer

Abstract

Introduction: Endotoxin (LPS) a cell wall constituent of gram-negative bacteria is a potent inflammatory stimulus. We have previously demonstrated that laparatomy is accompanied by increased growth of the primary tumour and pulmonary metastases and have implicated endotoxaemia (LPS) as a causative factor. Aims: We hypothesize that experimental use of the anti-endotoxin agent, rBPI21 (recombinant bactericidal permeability increasing protein) may block this LPS induced tumour response. Methods: 50,000 4T1 mammary adenocarcinoma cells were injected by lateral tail vein into female Balb/c mice to establish lung metastases. Mice were randomised into four groups (n = 5/group) to receive anaesthesia, laparotomy, laparotomy & rBPI21, laparotomy and control peptide, Thaumatin. Animals were sacrificed on day 14, lungs harvested and blood obtained. Tumour burden, tumour apoptosis, mitosis and plasma VEGF were measured. Conclusions: In an experimental metastases model, laparatomy resulted in increased metastatic burden and this was associated with increased tumour cell proliferation and apoptosis. LPS blockade by the anti-endotoxin agent rBPI21 attenuated this increased growth and was accompanied by decreased proliferation and increased apoptosis. VEGF may be a mediator of these effects. This data suggest that the anti endotoxin agent, rBPI21, has clinical potential as a novel therapeutic regime in the attenuation of surgery enhanced tumour growth and metastases especially in patients with a previous history of cancer undergoing laparotomy. TABLE—ABSTRACT P88Metastatic burdenMitotic indexApoptosisVEGF (pg/ml)Anaesthesia0.67 ± 0.0261.44 ± 0.134.37 ± 0.2821.14 ± 6.69Laparotomy1.13 ± 0.12∗5.29 ± 0.23∗1.12 ± 0.13∗213.56 ± 39.2∗rBPI21 & Laparotomy0.64 ± 0.02#1.61 ± 0.20#4.44 ± 0.39#39.69 ± 10.18#Thaumatin & Laparotomy1.13 ± 0.155.2 ± 0.204.44 ± 0.39184.87 ± 23.22Data is expressed as mean ± SEM (n = 5/group). ANOVA-post hoc statistical analysis.∗= P < 0.01 Laparotomy vs control.#= P < 0.02, rBPI21 & laparotomy vs. Laparotomy only.