Treatment of false‐negative metastatic lymph nodes by a lymphatic drug delivery system with 5‐fluorouracil

Abstract

Metastatic lymph nodes ( LN s) may be the origin of systemic metastases. It will be important to develop a strategy that prevents systemic metastasis by treating these LN s at an early stage. False‐negative metastatic LN s, which are found during the early stage of metastasis development, are those that contain tumor cells but have a size and shape similar to LN s that do not host tumor cells. Here, we show that 5‐fluorouracil (5‐ FU ), delivered by means of a novel lymphatic drug delivery system ( LDDS ), can treat LN s with false‐negative metastases in a mouse model. The effects of 5‐ FU on four cell lines were investigated using in vitro cytotoxicity and cell survival assays. The therapeutic effects of LDDS ‐administered 5‐ FU on false‐negative metastatic LN s were evaluated using bioluminescence imaging, high‐frequency ultrasound ( US ), and histology in MHX 10/Mo‐ lpr / lpr mice. These experimental animals develop LN s that are similar in size to human LN s. We found that all cell lines showed sensitivity to 5‐ FU in the in vitro assays. Furthermore, a concentration‐dependent effect of 5‐ FU to inhibit tumor growth was observed in tumor cells with low invasive growth characteristics, although a significant reduction in metastatic LN volume was not detected in MHX 10/Mo‐ lpr / lpr mice. Adverse effects of 5‐ FU were not detected. 5‐Fluorouracil administration with a LDDS is an effective treatment method for false‐negative metastatic LN s. We anticipate that the delivery of anticancer drugs by a LDDS will be of great benefit in the prevention and treatment of cancer metastasis via LN s.

Intranodal pressure of a metastatic lymph node reflects the response to lymphatic drug delivery system

“…KM‐Luc/GFP cells have low invasive growth characteristics and form tumor regions with well‐defined borders in or near the marginal sinuses. In contrast, FM3A cells have high invasive growth characteristics, proliferate along the trabecular sinus, and invade the cortex and paracortex 13,24 …”

Study of the physicochemical properties of drugs suitable for administration using a lymphatic drug delivery system

“…LNs have a rich vasculature, 3,4 and tumors can grow in LNs by replacing the parenchyma without the induction of tumor neovascularization 5,6 . This proliferative process generates focal perfusion defects that are detectable by contrast‐enhanced techniques such as ultrasound and computed tomography (CT) 7,8 . As tumor growth in a LN is not associated with tumor neovascularization and leads to a loss of blood vessels, it is likely that small‐molecule drugs or high–molecular‐weight drugs reliant on the enhanced permeability and retention effect 5,9 would not be effective treatments for lymphatic metastases when administered via the vascular system.…”

Formation of Perfusion Defects in Lymph Nodes During the Early Stage of Metastasis 

“…The concept of LN-mediated hematogenous metastasis implies that tumor cells spread from metastatic LNs to distant vital organs via blood vessels. Our group has recently developed a lymphatic drug delivery system (LDDS) that aims to treat sentinel LNs and their downstream LNs by injecting anticancer drugs directly into the sentinel LNs 8,35,36 . This therapeutic system can treat metastatic LNs using smaller doses of anticancer drug than is required for systemic chemotherapy.…”