ABSTRACT
The five-year survival rate for patients with head and neck squamous cell carcinoma (HNSCC) has remained at ~50% for the past 30 years despite advances in treatment. Tigilanol tiglate (TT, also known as EBC-46) is a novel diterpene ester that induces cell death in HNSCC in vitro and in mouse models, and has recently completed Phase I human clinical trials. The aim of this study was to optimise efficacy of TT treatment by altering different administration parameters. The tongue SCC cell line (SCC-15) was identified as the line with the lowest efficacy to treatment. Subcutaneous xenografts of SCC-15 cells were grown in BALB/c Foxn1nu and NOD/SCID mice and treated with intratumoral injection of 30 µg TT or a vehicle only control (40% propylene glycol (PG)). Greater efficacy of TT treatment was found in the BALB/c Foxn1nu mice compared to NOD/SCID mice. Immunohistochemical analysis indicated a potential role of the host's innate immune system in this difference, specifically neutrophil infiltration. Neither fractionated doses of TT nor the use of a different excipiant led to significantly increased efficacy. This study confirmed that TT in 40% PG given intratumorally as a single bolus dose was the most efficacious treatment for a tongue SCC mouse model.
Subject(s)
Carcinoma, Squamous Cell/drug therapy , Diterpenes/pharmacology , Neutrophil Infiltration/drug effects , Tongue Neoplasms/drug therapy , Animals , Apoptosis , Carcinoma, Squamous Cell/pathology , Cell Proliferation , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Inbred NOD , Mice, SCID , Tongue Neoplasms/pathology , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Mastitis in dairy heifers in the peripartum period is a common and costly problem for producers, and mammary innate resistance is of key importance in defense of the gland from bacterial invasion. A prospective observational study was undertaken in 97 dairy heifers to measure associations between expression of eight innate resistance factors in mammary secretions collected from the same animals within 14 days prior to calving and at calving, and intramammary infection (IMI) status at calving, and to describe changes in expression of these factors over time. Relative expression (RE) of eight candidate resistance mediator genes from cells from intramammary secretion was measured by quantitative real time polymerase chain reaction. Glands which were IMI-free pre-calving and did not develop a new IMI had significantly higher RE of molecule possessing ankyrin-repeat (MAIL) and beta defensin (Bdef) genes compared to glands which subsequently did develop a new IMI. Also, Bdef RE increased up to the day of calving in glands that did not develop a new IMI, but was unresponsive in glands that did develop a new IMI. Relative expression of complement 5 alpha receptor, interleukin 1beta and interleukin 8 increased in glands that did develop a new IMI. Serum amyloid A3 and toll-like receptor 2 RE increased in all glands up to the day of calving. Transforming growth factor beta RE was not associated with new infection status or time relative to calving. These findings support further investigation of function and gene polymorphisms of MAIL and Bdef as potential markers of mastitis resistance in dairy heifers.
