Eelco F J Meijer1,2, Cedric Blatter2,3, Ivy X Chen1,2, Echoe Bouta1,2, Dennis Jones1,2, Ethel R Pereira1,2, Keehoon Jung1,2, Benjamin J Vakoc2,3, James W Baish4, Timothy P Padera1,2. 1. Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA. 2. Harvard Medical School, Boston, MA, USA. 3. Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA. 4. Department of Biomedical Engineering, Bucknell University, Lewisburg, PA, USA.
Abstract
OBJECTIVE: 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. METHODS: 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. RESULTS: VEGF-A-treated lymph node blood vessel effective vascular permeability (mean 3.83 × 10-7 cm/s) was significantly higher than untreated lymph nodes (mean 9.87 × 10-8 cm/s). No difference was found in lymph node drug accumulation in untreated versus VEGF-A-treated mice. CONCLUSIONS: 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.
OBJECTIVE: 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. METHODS: 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. RESULTS:VEGF-A-treated lymph node blood vessel effective vascular permeability (mean 3.83 × 10-7 cm/s) was significantly higher than untreated lymph nodes (mean 9.87 × 10-8 cm/s). No difference was found in lymph node drug accumulation in untreated versus VEGF-A-treated mice. CONCLUSIONS: 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.
Authors: Han-Sin Jeong; Dennis Jones; Shan Liao; Daniel A Wattson; Cheryl H Cui; Dan G Duda; Christopher G Willett; Rakesh K Jain; Timothy P Padera Journal: J Natl Cancer Inst Date: 2015-06-10 Impact factor: 13.506
Authors: G Bocci; R Danesi; A D Di Paolo; F Innocenti; G Allegrini; A Falcone; A Melosi; M Battistoni; G Barsanti; P F Conte; M Del Tacca Journal: Clin Cancer Res Date: 2000-08 Impact factor: 12.531
Authors: W L Monsky; D Fukumura; T Gohongi; M Ancukiewcz; H A Weich; V P Torchilin; F Yuan; R K Jain Journal: Cancer Res Date: 1999-08-15 Impact factor: 12.701
Authors: Benjamin J Vakoc; Ryan M Lanning; James A Tyrrell; Timothy P Padera; Lisa A Bartlett; Triantafyllos Stylianopoulos; Lance L Munn; Guillermo J Tearney; Dai Fukumura; Rakesh K Jain; Brett E Bouma Journal: Nat Med Date: 2009-09-13 Impact factor: 53.440