Meijer Eelco F J, Blatter Cedric, Chen Ivy X, Bouta Echoe, Jones Dennis, Pereira Ethel R, Jung Keehoon, Vakoc Benjamin J, Baish James W, Padera Timothy P
Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Microcirculation. 2017 Aug;24(6). doi: 10.1111/micc.12381.
Lymph node metastases are a poor prognostic factor. Additionally, responses of lymph node metastasis to therapy can be different from the primary tumor. Investigating the physiologic lymph node blood vasculature might give insight into the ability of systemic drugs to penetrate the lymph node, and thus into the differential effect of therapy between lymph node metastasis and primary tumors. Here, we measured effective vascular permeability of lymph node blood vessels and attempted to increase chemotherapy penetration by increasing effective vascular permeability.
We developed a novel three-dimensional method to measure effective vascular permeability in murine lymph nodes in vivo. VEGF-A was systemically administered to increase effective vascular permeability. Validated high-performance liquid chromatography protocols were used to measure chemotherapeutic drug concentrations in untreated and VEGF-A-treated lymph nodes, liver, spleen, brain, and blood.
VEGF-A-treated lymph node blood vessel effective vascular permeability (mean 3.83 × 10 cm/s) was significantly higher than untreated lymph nodes (mean 9.87 × 10 cm/s). No difference was found in lymph node drug accumulation in untreated versus VEGF-A-treated mice.
Lymph node effective vascular permeability can be increased (~fourfold) by VEGF-A. However, no significant increase in chemotherapy uptake was measured by pretreatment with VEGF-A.
淋巴结转移是一个不良预后因素。此外，淋巴结转移对治疗的反应可能与原发肿瘤不同。研究生理性淋巴结血管系统可能有助于深入了解全身药物穿透淋巴结的能力，进而了解淋巴结转移和原发肿瘤之间治疗效果的差异。在此，我们测量了淋巴结血管的有效血管通透性，并试图通过增加有效血管通透性来提高化疗药物的渗透。
我们开发了一种新颖的三维方法来测量小鼠体内淋巴结的有效血管通透性。全身给予血管内皮生长因子-A（VEGF-A）以增加有效血管通透性。使用经过验证的高效液相色谱方法来测量未治疗和VEGF-A治疗的淋巴结、肝脏、脾脏、大脑和血液中的化疗药物浓度。
VEGF-A治疗的淋巴结血管有效血管通透性（平均3.83×10 cm/s）显著高于未治疗的淋巴结（平均9.87×10 cm/s）。在未治疗与VEGF-A治疗的小鼠中，淋巴结药物蓄积未发现差异。
VEGF-A可使淋巴结有效血管通透性增加（约四倍）。然而，VEGF-A预处理并未使化疗药物摄取量显著增加。
