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Doxorubicin Acutely Inhibits Lymph Flow in Rat Mesenteric Lymph Vessels

Arm lymphedema is a major complication after surgery and/or radiation for breast cancer. This life‐long and disfiguring complication can cause serious medical problems including lymphangitis, cellulitis, and other recurrent infections. Doxorubicin (DOX) is often a central component in chemotherapy to prevent metastases or recurrence of breast cancer, but this cytotoxic drug increases the incidence and severity of lymphedema as an off‐target effect. Interestingly, the mechanisms by which DOX contributes to arm lymphedema have not been elucidated. We hypothesized that DOX directly suppresses lymphatic drainage by disrupting lymph vessel (LV) contractile function. Rats were anesthetized and one loop of mesentery was exposed on a heated microscope stage. High‐resolution optical imaging of rat mesenteric LVs in vivo revealed that continuous superfusion of DOX (0.05 to 10 μmol/L) progressively reduced positive volumetric lymph flow to ~30% of baseline (t=20 min, n=6) with an IC50 of 0.66 μmol/L. This effect of DOX was partially reversed by drug washout. Data were corrected for solvent and time controls (n=5–6). In a subsequent study, baseline measurements were recorded for 10 min, and then rats were injected via tail vein with a clinically relevant dose of DOX (10 mg/kg) or equivalent volume of saline. Mesenteric lymph flow was measured continuously for 2 hr post‐injection. At 0.75–1.25 hr post‐ injection, DOX significantly reduced positive volumetric flow to ~45% of baseline, whereas saline injection increased positive volumetric flow by ~35% from baseline (n=4–5). HPLC was used to determine corresponding DOX plasma levels during the measurement period. The average plasma concentration of DOX was 0.15±0.06 μmol/L (86 ± 34 ng/mL) and 0.10±0.02 μmol/L (59±13 ng/mL) at 1 and 2 hr after injection, respectively (n=5). These values were similar to DOX concentrations used in the superfusate studies and equivalent to plasma DOX concentrations achieved during chemotherapy in patients. Thus, clinically relevant concentrations of DOX appear to directly and acutely inhibit LV contractile function in vivo, and the resulting compromise of lymph flow represents a possible contributing mechanism of drug‐induced lymphedema.