Effects of tin-protoporphyrin IX on blood flow in a rat tumor model.
Carbon monoxide (CO), one of the products of heme oxygenase (HO) catalyzed heme degradation, is a vasodilator. The aim of the present study was to clarify the role of HO in blood flow maintenance in tumors. Male BD9 rats bearing subcutaneous transplants of the P22 carcinosarcoma tumor were treated intraperitoneally (i.p.) with either tin-protoporphyrin IX (SnPP; 45 micromol/kg), a selective inhibitor of HO or copper-protoporphyrin IX (CuPP; 45 micromol/kg), used as a negative control. The extent of HO activity inhibition was measured using a spectrophotometric assay of bilirubin production and blood flow rates to the tumor and a range of normal tissues were assessed using the uptake of the radiolabelled tracer, iodo-antipyrine ((125)I-IAP). The animals were cannulated under fentanyl citrate/fluanisone (Hypnorm)/midazolam anesthesia. In the P22 tumor, SnPP, but not CuPP, caused a complete inhibition of HO activity 15 min post-treatment. Administration of SnPP 15 min before blood flow measurements reduced tumor blood flow by 17%, with no effects in any of the normal tissues studied. However, CuPP induced a greater reduction in tumor blood flow than SnPP (45% decrease). Furthermore, CuPP caused a reduction in blood flow to the skin and small intestine but a significant increase to skeletal muscle. The current findings conclusively establish only a minor role played by the HO/CO system in the maintenance of blood flow in this tumor system, despite relatively high levels of HO-1 protein and HO activity. The results also highlight the potential usefulness of CuPP as a tumor blood flow modifier.
Khelifi
Amel F
AF
Tumor Microcirculation Group, Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex HA6 2JR, United Kingdom. khelifi@gci.ac.uk
Prise
Vivien E
VE
Tozer
Gillian M
GM
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D002248:Carbon Monoxide / Q000378:metabolism*; D002296:Carcinosarcoma / Q000098:blood supply* / Q000201:enzymology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D011524:Protoporphyrins / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012039:Regional Blood Flow / Q000187:drug effects
D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D011524:Protoporphyrins; C092553:copper protoporphyrin IX; D002248:Carbon Monoxide; C032628:tin protoporphyrin IX; D006419:Heme Oxygenase (Decyclizing)