Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Cancer Res. 2010 Nov 15;70(22):9319-28. doi: 10.1158/0008-5472.CAN-10-1783. Epub 2010 Nov 9.
Metastatic ovarian cancer (OvCa) frequently recurs due to chemoresistance, highlighting the need for nonoverlapping combination therapies that mechanistically synergize to eradicate residual disease. Photodynamic therapy (PDT), a photochemistry-based cytotoxic modality, sensitizes ovarian tumors to platinum agents and biologics and has shown clinical promise against ovarian carcinomatosis. We introduce a three-dimensional (3D) model representing adherent ovarian micrometastases and high-throughput quantitative imaging methods to rapidly screen the order-dependent effects of combining benzoporphyrin-derivative (BPD) monoacid A-based PDT with low-dose carboplatin. 3D ovarian micronodules grown on Matrigel were subjected to BPD-PDT either before or after carboplatin treatment. We developed custom fluorescence image analysis routines to quantify residual tumor volume and viability. Carboplatin alone did not eradicate ovarian micrometastases at a dose of 400 mg/m2, leaving surviving cores that were nonsensitive or impermeable to chemotherapy. BPD-PDT (1.25 μmol/L·J/cm2) created punctate cytotoxic regions within tumors and disrupted micronodular structure. Treatment with BPD-PDT prior to low-dose carboplatin (40 mg/m2) produced a significant synergistic reduction [P<0.0001, analysis of covariance (ANCOVA)] in residual tumor volume [0.26; 95% confidence interval (95% CI), 0.19-0.36] compared with PDT alone (0.76; 95% CI, 0.63-0.92) or carboplatin alone (0.95; 95% CI, 0.83-1.09), relative to controls. This synergism was not observed with the reverse treatment order. Here, we demonstrate for the first time the use of a 3D model for micrometastatic OvCa as a rapid and quantitative reporter to optimize sequence and dosing regimens of clinically relevant combination strategies. This approach combining biological modeling with high-content imaging provides a platform to rapidly screen therapeutic strategies for a broad array of metastatic tumors.
转移性卵巢癌（OvCa）经常由于化疗耐药而复发，这突出表明需要使用非重叠的联合治疗方法，这些方法在机制上协同作用以根除残留疾病。光动力疗法（PDT）是一种基于光化学的细胞毒性方式，可使卵巢肿瘤对铂类药物和生物制剂敏感，并已显示出对卵巢癌转移的临床潜力。我们引入了一种代表贴壁卵巢微转移的三维（3D）模型和高通量定量成像方法，以快速筛选联合苯并卟啉衍生物（BPD）单酸 A 基 PDT 与低剂量卡铂的顺序依赖性效应。在 Matrigel 上生长的 3D 卵巢微结节先接受 BPD-PDT 治疗，然后再接受卡铂治疗。我们开发了自定义荧光图像分析例程来量化残留肿瘤体积和活力。在 400mg/m2 的剂量下，卡铂单独使用并不能根除卵巢微转移，留下对化疗不敏感或不可渗透的存活核心。BPD-PDT（1.25μmol/L·J/cm2）在肿瘤内产生点状细胞毒性区域，并破坏微结节结构。与单独使用 PDT（0.76；95%置信区间（95%CI），0.63-0.92）或单独使用卡铂（0.95；95%CI）相比，在低剂量卡铂（40mg/m2）之前进行 BPD-PDT 治疗可显著协同降低残留肿瘤体积[P<0.0001，协方差分析（ANCOVA）] [0.26；95%CI，0.19-0.36]，与对照组相比。这种协同作用在相反的治疗顺序中没有观察到。在这里，我们首次证明了使用 3D 模型作为微小转移性 OvCa 的快速和定量报告器，以优化临床相关联合策略的顺序和剂量方案。这种将生物建模与高内涵成像相结合的方法为快速筛选广泛转移性肿瘤的治疗策略提供了一个平台。
