Khelifi Amel F, Prise Vivien E, Tozer Gillian M
Tumor Microcirculation Group, Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex HA6 2JR, United Kingdom.
Exp Biol Med (Maywood). 2003 May;228(5):481-5. doi: 10.1177/15353702-0322805-10.
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.
一氧化碳（CO）是血红素加氧酶（HO）催化血红素降解的产物之一，是一种血管舒张剂。本研究的目的是阐明HO在肿瘤血流维持中的作用。将携带P22癌肉瘤皮下移植瘤的雄性BD9大鼠腹腔内注射锡原卟啉IX（SnPP；45微摩尔/千克），一种HO的选择性抑制剂，或铜原卟啉IX（CuPP；45微摩尔/千克）作为阴性对照。使用胆红素生成的分光光度测定法测量HO活性抑制程度，并使用放射性标记示踪剂碘安替比林（（125）I-IAP）的摄取来评估肿瘤和一系列正常组织的血流速率。动物在枸橼酸芬太尼/氟胺酮（Hypnorm）/咪达唑仑麻醉下插管。在P22肿瘤中，SnPP而非CuPP在治疗后15分钟导致HO活性完全抑制。在血流测量前15分钟给予SnPP使肿瘤血流减少17%，对所研究的任何正常组织均无影响。然而，CuPP比SnPP诱导更大程度的肿瘤血流减少（减少45%）。此外，CuPP导致皮肤和小肠血流减少，但骨骼肌血流显著增加。目前的研究结果最终确定，尽管HO-1蛋白水平和HO活性相对较高，但HO/CO系统在该肿瘤系统的血流维持中仅起次要作用。结果还突出了CuPP作为肿瘤血流调节剂的潜在用途。
