Doxorubicin inhibits lymphatic function in vitro and in vivo (655.1)

Abstract

Doxorubicin (DOX) is an independent risk factor for lymphedema in breast cancer patients after surgery and/or radiation therapy. The mechanisms by which DOX contributes to lymphedema are unclear. We hypothesized that DOX directly inhibits lymphatic contractions and lymph flow by a mechanism distinct from its cytotoxic action. Isolated rat mesenteric lymph vessels (LVs) were cannulated, pressurized (4‐5 mm Hg) and equilibrated in a no‐flow system using physiological salt solution (37°C) until spontaneous contractions were stable. An edge‐detection system recorded changes in external diameter. Adding DOX into the bath at increasing concentrations (0.5 to 20 µmol/L; n=7) progressively attenuated the amplitude and area under the curve (AUC) of LV contractions, culminating in reductions of ~55% (amplitude) and ~60% (AUC). Washout of DOX partially restored contractile activity. High‐resolution, intravital optical imaging of rat mesenteric LVs in vivo also revealed that DOX (10 µmol/L) inhibits LV spontaneous contractions and reduces lymph flow (n=2). DOX reduced lymph flow by ~66% (t=10 min) and 100% (t=30 min) from baseline. Thus, DOX may contribute to lymphedema by directly inhibiting LV contractile function as an off‐target effect.Grant Funding Source: Partially supported by a Rho Chi‐AFPE Graduate Fellowship (AS)