Department of Radiation Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
Transl Oncol. 2010 Oct 1;3(5):293-306. doi: 10.1593/tlo.10136.
In an attempt to develop better therapeutic approaches for metastatic renal cell carcinoma (RCC), the combination of the antiangiogenic drug sunitinib with gemcitabine was studied. Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), we have previously determined that a sunitinib dosage of 20 mg/kg per day increased kidney tumor perfusion and decreased vascular permeability in a preclinical murine RCC model. This sunitinib dosage causing regularization of tumor vessels was selected to improve delivery of gemcitabine to the tumor. DCE-MRI was used to monitor regularization of vasculature with sunitinib in kidney tumors to schedule gemcitabine. We established an effective and nontoxic schedule of sunitinib combined with gemcitabine consisting of pretreatment with sunitinib for 3 days followed by four treatments of gemcitabine at 20 mg/kg given 3 days apart while continuing daily sunitinib treatment. This treatment caused significant tumor growth inhibition resulting in small residual tumor nodules exhibiting giant tumor cells with degenerative changes, which were observed both in kidney tumors and in spontaneous lung metastases, suggesting a systemic antitumor response. The combined therapy caused a significant increase in mouse survival. DCE-MRI monitoring of vascular changes induced by sunitinib, gemcitabine, and both combined showed increased tumor perfusion and decreased vascular permeability in kidney tumors. These findings, confirmed histologically by thinning of tumor blood vessels, suggest that both sunitinib and gemcitabine exert antiangiogenic effects in addition to cytotoxic antitumor activity. These studies show that DCE-MRI can be used to select the dose and schedule of antiangiogenic drugs to schedule chemotherapy and improve its efficacy.
为了开发转移性肾细胞癌 (RCC) 的更好治疗方法,研究了将抗血管生成药物舒尼替尼与吉西他滨联合使用。使用动态对比增强磁共振成像 (DCE-MRI),我们之前已经确定,每天 20 毫克/公斤的舒尼替尼剂量可增加临床前 RCC 模型中的肾脏肿瘤灌注并降低血管通透性。选择这种导致肿瘤血管正常化的舒尼替尼剂量是为了改善吉西他滨向肿瘤的输送。DCE-MRI 用于监测舒尼替尼对肾脏肿瘤血管的正常化作用,以安排吉西他滨的治疗。我们建立了一种有效且无毒的舒尼替尼联合吉西他滨方案,包括舒尼替尼预处理 3 天,然后间隔 3 天给予 4 次 20 毫克/公斤的吉西他滨,同时继续每天给予舒尼替尼治疗。这种治疗方法导致肿瘤生长明显抑制,导致残留的小肿瘤结节表现出具有退行性变化的巨大肿瘤细胞,在肾脏肿瘤和自发性肺转移中均观察到,提示存在全身性抗肿瘤反应。联合治疗显著提高了小鼠的存活率。DCE-MRI 监测舒尼替尼、吉西他滨和两者联合引起的血管变化显示,肾脏肿瘤中的肿瘤灌注增加,血管通透性降低。这些发现通过肿瘤血管变薄在组织学上得到证实,表明舒尼替尼和吉西他滨除了具有细胞毒性抗肿瘤活性外,还具有抗血管生成作用。这些研究表明,DCE-MRI 可用于选择抗血管生成药物的剂量和方案来安排化疗并提高其疗效。