Pietras Kristian, Rubin Kristofer, Sjöblom Tobias, Buchdunger Elisabeth, Sjöquist Mats, Heldin Carl-Henrik, Ostman Arne
Ludwig Institute for Cancer Research, SE-751 24 Uppsala, Sweden.
Cancer Res. 2002 Oct 1;62(19):5476-84.
Lowering of tumor interstitial hypertension, which acts as a barrier for tumor transvascular transport, has been proposed as a general strategy to enhance tumor uptake and therapeutic effects of anticancer drugs. The tyrosine kinase platelet-derived growth factor (PDGF) beta-receptor is one mediator of tumor hypertension. The effects of PDGF antagonists on chemotherapy response were investigated in two tumor models that display PDGF receptor expression restricted to the tumor stroma, and in which PDGF antagonists relieve tumor hypertension. Inhibitory PDGF aptamers and the PDGF receptor tyrosine kinase inhibitor STI571 enhanced the antitumor effect of Taxol on s.c. KAT-4 tumors in SCID mice. Treatment with only PDGF antagonists had no effect on tumor growth. Taxol uptake in tumors was increased by treatment with PDGF antagonists. Cotreatment with PDGF antagonists and Taxol was not associated with antiangiogenic effects, and PDGF antagonists did not enhance the Taxol effect on in vitro growth of KAT-4 cells. STI571 also increased the antitumor effects of 5-fluorouracil on s.c. PROb tumors in syngeneic BDIX rats, without increasing the effect of 5-fluorouracil on cultured PROb cells. Expression of PDGF receptors in tumor stroma, as well as tumor hypertension, occurs in most common solid tumors. Therefore, our results have implications for treatment regimens for large patient groups and merit clinical testing. In conclusion, our study identifies inhibition of PDGF signaling in tumor stroma as a novel, possibly general strategy for enhancement of the therapeutic effects chemotherapy.
降低肿瘤间质高血压被认为是增强抗癌药物肿瘤摄取和治疗效果的一种通用策略，因为肿瘤间质高血压是肿瘤跨血管运输的障碍。酪氨酸激酶血小板衍生生长因子（PDGF）β受体是肿瘤高血压的介质之一。在两种肿瘤模型中研究了PDGF拮抗剂对化疗反应的影响，这两种模型中PDGF受体表达局限于肿瘤基质，且PDGF拮抗剂可缓解肿瘤高血压。抑制性PDGF适配体和PDGF受体酪氨酸激酶抑制剂STI571增强了紫杉醇对SCID小鼠皮下KAT-4肿瘤的抗肿瘤作用。仅用PDGF拮抗剂治疗对肿瘤生长无影响。用PDGF拮抗剂治疗可增加肿瘤对紫杉醇的摄取。PDGF拮抗剂与紫杉醇联合治疗与抗血管生成作用无关，且PDGF拮抗剂未增强紫杉醇对KAT-4细胞体外生长的作用。STI571还增强了5-氟尿嘧啶对同基因BDIX大鼠皮下PROb肿瘤的抗肿瘤作用，而未增加5-氟尿嘧啶对培养的PROb细胞的作用。肿瘤基质中PDGF受体的表达以及肿瘤高血压在大多数常见实体瘤中均存在。因此，我们的结果对大量患者群体的治疗方案具有启示意义，值得进行临床试验。总之，我们的研究确定抑制肿瘤基质中的PDGF信号传导是增强化疗治疗效果的一种新的、可能通用的策略。
