PMID- 18953175 OWN - NLM STAT- MEDLINE DCOM- 20090505 LR - 20141120 IS - 1423-0135 (Electronic) IS - 1018-1172 (Linking) VI - 46 IP - 3 DP - 2009 TI - Styrene maleic acid-pirarubicin disrupts tumor microcirculation and enhances the permeability of colorectal liver metastases. PG - 218-28 LID - 10.1159/000165380 [doi] AB - BACKGROUND: Doxorubicin is a commonly used chemotherapy limited by cardiotoxicity. Pirarubicin, derived from doxorubicin, selectively targets tumors when encapsulated in styrene maleic acid (SMA), forming the macromolecular SMA pirarubicin. Selective targeting is achieved because of the enhanced permeability and retention (EPR) effect. SMA-pirarubicin inhibits the growth of colorectal liver metastases, but tumor destruction is incomplete. The role played by the tumor microcirculation is uncertain. This study investigates the pattern of microcirculatory changes following SMA-pirarubicin treatment. METHODS: Liver metastases were induced in CBA mice using a murine-derived colon cancer line. SMA-pirarubicin (100 mg/kg total dose) was administered intravenously in 3 separate doses. Twenty-four hours after chemotherapy, the tumor microvasculature was examined using CD34 immunohistochemistry and scanning electron microscopy. Tumor perfusion and permeability were assessed using confocal in vivo microscopy and the Evans blue method. RESULTS: SMA-pirarubicin reduced the microvascular index by 40%. Vascular occlusion and necrosis were extensive following treatment. Viable cells were arranged around tumor vessels. Tumor permeability was also increased. CONCLUSION: SMA-pirarubicin damages tumor cells and the tumor microvasculature and enhances tumor vessel permeability. However, tumor necrosis is incomplete, and the growth of residual cells is sustained by a microvascular network. Combined therapy with a vascular targeting agent may affect residual cells, allowing more extensive destruction of tumors. CI - Copyright (c) 2008 S. Karger AG, Basel. FAU - Daruwalla, Jurstine AU - Daruwalla J AD - Department of Surgery, University of Melbourne, Austin Hospital, Studley Road, Heidelberg, Victoria 3084, Australia. jurstine@pgrad.unimelb.edu.au FAU - Greish, Khaled AU - Greish K FAU - Malcontenti-Wilson, Cathy AU - Malcontenti-Wilson C FAU - Muralidharan, Vijayaragavan AU - Muralidharan V FAU - Iyer, Arun AU - Iyer A FAU - Maeda, Hiroshi AU - Maeda H FAU - Christophi, Chris AU - Christophi C LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20081027 PL - Switzerland TA - J Vasc Res JT - Journal of vascular research JID - 9206092 RN - 0 (Antigens, CD34) RN - 0 (Antineoplastic Agents) RN - 0 (Maleates) RN - 44LJ2U959V (Styrene) RN - 80168379AG (Doxorubicin) RN - 91XW058U2C (maleic acid) RN - D58G680W0G (pirarubicin) SB - IM MH - Animals MH - Antigens, CD34/analysis MH - Antineoplastic Agents/*administration & dosage MH - Colorectal Neoplasms/blood supply/*drug therapy/pathology MH - Doxorubicin/administration & dosage/*analogs & derivatives MH - Drug Delivery Systems MH - Immunohistochemistry MH - Liver Neoplasms, Experimental/*secondary MH - Male MH - Maleates/*administration & dosage MH - Mice MH - Mice, Inbred CBA MH - Microcirculation/drug effects MH - Microscopy, Confocal MH - Necrosis MH - Permeability MH - Styrene/*administration & dosage EDAT- 2008/10/28 09:00 MHDA- 2009/05/06 09:00 CRDT- 2008/10/28 09:00 PHST- 2008/02/02 00:00 [received] PHST- 2008/04/12 00:00 [accepted] PHST- 2008/10/28 09:00 [pubmed] PHST- 2009/05/06 09:00 [medline] PHST- 2008/10/28 09:00 [entrez] AID - 000165380 [pii] AID - 10.1159/000165380 [doi] PST - ppublish SO - J Vasc Res. 2009;46(3):218-28. doi: 10.1159/000165380. Epub 2008 Oct 27.