Histamine, a vasoactive agent with vascular disrupting potential, improves tumour response by enhancing local drug delivery

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

Induction of endothelin secretion by angiotensin II: Effects on growth and synthetic activity of vascular smooth muscle cells

Angiotensin II induces the synthesis and secretion of endothelin by cultured rat vascular smooth muscle cells. Previous studies demonstrate that angiotensin II also activates the synthesis of extracellular matrix-associated glycoconjugates (glycopeptides and proteoglycans) by cultured smooth muscle cells. Furthermore, in culture medium containing mitogen-depleted, plasma-derived serum (1.0%), angiotensin II stimulates the growth of rat smooth muscle cells. Therefore, the influence of endothelin-1 (ET-1) on the growth and matrix elaboration by cultured rat smooth muscle cells was studied to assess its contribution to the stimulatory activity of angiotensin II. In quiescent cultures of smooth muscle cells, no stimulation of the incorporation of [3H]thymidine into DNA by ET-1 was apparent, even at maximal doses (10-7 M). Under the same conditions, the synthesis of extracellular matrix glycoconjugate material was not enhanced by ET-1, unlike angiotensin II. In cultures maintained in medium containing 1.0% plasma-derived serum, ET-1 was incapable of stimulating either proliferation or incorporation of [3H]thymidine into DNA whereas angiotensin II stimulated both activities. ET-1, however, did induce the expression of growth factor and thrombospondin genes in quiescent smooth muscle cultures. The data suggest that growth stimulation of smooth muscle cells by angiotensin II does not occur as a consequence of stimulated ET-1 production.link_to_subscribed_fulltex