title: Histamine, a vasoactive agent with vascular disrupting potential, improves tumour response by enhancing local drug delivery.
abstract: Tumour necrosis factor (TNF)-based isolated limb perfusion (ILP) is an approved and registered treatment for sarcomas confined to the limbs in Europe since 1998, with limb salvage indexes of 76%. TNF improves drug distribution in solid tumours and secondarily destroys the tumour-associated vasculature (TAV). Here we explore the synergistic antitumour effect of another vasoactive agent, histamine (Hi), in doxorubicin (DXR)-based ILP and evaluate its antivascular effects on TAV. We used our well-established rat ILP model for in vivo studies looking at tumour response, drug distribution and effects on tumour vessels. In vitro studies explored drug interactions at cellular level on tumour cells (BN-175) and Human umbilical vein endothelial cells (HUVEC). There was a 17% partial response and a 50% arrest in tumour growth when Hi was combined to DXR, without important side effects, against 100% progressive disease with DXR alone and 29% arrest in tumour growth for Hi alone. Histology documented an increased DXR leakage in tumour tissue combined to a destruction of the TAV, when Hi was added to the ILP. In vitro no synergy between the drugs was observed. In conclusion, Hi is a vasoactive drug, targeting primarily the TAV and synergises with different chemotherapeutic agents.
authors.affiliation: Laboratory of Experimental Surgical Oncology, Erasmus MC, Department of Surgical Oncology, Daniel den Hoed Cancer Centre, Room Ee 0175, PO Box 1738-3000 DR Rotterdam, The Netherlands. flis_br@yahoo.com
authors.forename: F
authors.initials: F
authors.lastname: Brunstein
authors.forename: J
authors.initials: J
authors.lastname: Rens
authors.forename: S T
authors.initials: ST
authors.lastname: van Tiel
authors.forename: A M M
authors.initials: AM
authors.lastname: Eggermont
authors.forename: T L M
authors.initials: TL
authors.lastname: ten Hagen
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology; D002478:Cells, Cultured; D010478:Chemotherapy, Cancer, Regional Perfusion; D004317:Doxorubicin / Q000494:pharmacology; D016503:Drug Delivery Systems; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006614:Hindlimb; D006632:Histamine / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D012509:Sarcoma / Q000098:blood supply / Q000188:drug therapy*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D002317:Cardiovascular Agents; D004317:Doxorubicin; D006632:Histamine