Sarkar Chandrani, Chakroborty Debanjan, Dasgupta Partha Sarathi, Basu Sujit
Department of Pathology, Ohio State University, Columbus, OH.
Chittaranjan National Cancer Institute, Kolkata, 700026, India.
Int J Cancer. 2015 Aug 1;137(3):744-9. doi: 10.1002/ijc.29414. Epub 2015 Jan 7.
The role of vascular endothelial growth factor A (VEGFA) in tumor angiogenesis is well established and accordingly, molecules targeting VEGFA or its receptors are being presently used in the clinics for treatment of several types of cancer. However, these antiangiogenic agents are expensive and have serious side effects. Thus identification of newer drugs with manageable systemic side effects or toxicities is of immense clinical importance. Since we have reported earlier that dopamine (DA) inhibits VEGFA induced angiogenesis in experimental tumor models, we therefore sought to investigate whether DA treatment results in similar toxicities like other antiangiogenic agents. Our results indicated that unlike sunitinib, another commonly used antiangiogenic agent in the clinics which targets VEGF receptors, DA [50 mg/kg/days × 7days intraperitoneally (i.p.)] not only could inhibit tumor angiogenesis and growth of HT29 human colon cancer and LLC (Lewis lung carcinoma) in mice, it also did not cause hypertension, hematological, renal and hepatic toxicities in normal, HT29 and LLC tumor bearing animals. Furthermore and interestingly, in contrast to the currently used antiangiogenic agents, DA also prevented 5-fluorouracil (5FU) induced neutropenia in HT29 colon cancer bearing mice. This action of DA was through inhibition of 5FU mediated suppression of colony forming unit-granulocyte macrophage colony forming units in the bone marrow. Thus our results indicate that DA may be safely used as an antiangiogenic drug for the treatment of malignant tumors.
血管内皮生长因子A(VEGFA)在肿瘤血管生成中的作用已得到充分证实,因此,目前临床上正在使用靶向VEGFA或其受体的分子来治疗多种类型的癌症。然而,这些抗血管生成药物价格昂贵且有严重的副作用。因此,鉴定具有可控全身副作用或毒性的新型药物具有极其重要的临床意义。由于我们之前报道过多巴胺(DA)在实验性肿瘤模型中可抑制VEGFA诱导的血管生成,因此我们试图研究DA治疗是否会导致与其他抗血管生成药物类似的毒性。我们的结果表明,与临床上另一种常用的靶向VEGF受体的抗血管生成药物舒尼替尼不同,DA[50mg/kg/天×7天腹腔内(i.p.)给药]不仅可以抑制小鼠体内HT29人结肠癌和LLC(刘易斯肺癌)的肿瘤血管生成和生长,而且在正常小鼠、荷HT29肿瘤小鼠和荷LLC肿瘤小鼠中也不会引起高血压、血液学、肾脏和肝脏毒性。此外,有趣的是,与目前使用的抗血管生成药物相比,DA还可预防荷HT29结肠癌小鼠中5-氟尿嘧啶(5FU)诱导的中性粒细胞减少。DA的这种作用是通过抑制5FU介导的骨髓中集落形成单位-粒细胞巨噬细胞集落形成单位的抑制来实现的。因此,我们的结果表明,DA可安全地用作治疗恶性肿瘤的抗血管生成药物。