Photoimmunotherapy and biodistribution with an OC125-chlorin immunoconjugate in an in vivo murine ovarian cancer model.
Photoimmunotherapy and biodistribution with an OC125-chlorin immunoconjugate in an in vivo murine ovarian cancer model.
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DOI：
10.1038/bjc.1994.330
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发表时间：
1994-09
影响因子：
8.8
通讯作者：
Hasan, T
中科院分区：
文献类型：
--
作者：
Goff, B A;Hermanto, U;Rumbaugh, J;Blake, J;Bamberg, M;Hasan, T
光动力疗法（PDT）是一种治疗肿瘤的实验方法，其中积聚在恶性组织中的光敏剂（PS）被适当波长的光光激活。PS的靶特异性可以通过将它们与载体大分子如单克隆抗体（MAb）连接来改善。OC 125是一种识别抗原CA 125的鼠单克隆抗体，CA 125在80%的非粘液性卵巢肿瘤中表达。偶联到OC 125的二氢卟酚衍生物显示出在体外和离体对卵巢癌和其它CA 125阳性细胞具有选择性光毒性。我们现在报告使用腹水Balb/c裸鼠卵巢癌模型的体内研究。通过腹膜内注射来自人卵巢癌细胞系NIH：OVCAR 3的细胞诱导腹水。注射后6周，当动物出现腹水时，通过腹膜内注射免疫缀合物（IC）或游离PS并在3、6、12、24、48、72和168小时后处死动物来进行生物分布研究。通过萃取和荧光光谱法定量PS。对于IC和游离PS，在24小时达到峰值肿瘤浓度;然而，IC的绝对浓度始终高于游离PS（2- 3倍）。IC在24小时的肿瘤与非肿瘤比率为血液6.8、肝脏6.5、肾脏7.2、皮肤5.7和肠3.5。在体内PDT与单次曝光后，腹水中的活肿瘤细胞的评价显示出与通量和IC浓度的剂量依赖性关系。然而，在所有剂量下均存在显著的给药相关毒性。通过多次低剂量治疗，存活肿瘤细胞的百分比也显著降低，并且没有治疗相关的死亡。这些数据表明，虽然光免疫疗法作为卵巢癌的一种新的治疗方式仍然很有前途，但IC和光的仔细定量剂量测定可能需要与多种治疗（如放疗和化疗）相结合，以控制恶性疾病，同时保持可接受的体内毒性。
Photodynamic therapy (PDT) is an experimental approach to the treatment of neoplasms in which photosensitisers (PSs) accumulated in malignant tissues are photoactivated with appropriate wavelengths of light. The target specificity of PSs may be improved by linking them with carrier macromolecules such as monoclonal antibodies (MAbs). OC125 is a murine MAb that recognises the antigen CA 125, which is expressed on 80% of non-mucinous ovarian tumours. A chlorin derivative conjugated to OC125 was shown to be selectively phototoxic to ovarian cancer and other CA 125-positive cells in vitro and ex vivo. We now report in vivo studies using an ascitic Balb/c nude mouse ovarian cancer model. Ascites was induced by intraperitoneal injection of cells from the human ovarian cancer cell line NIH:OVCAR3. Six weeks after injection, when the animals had developed ascites, biodistribution studies were carried out by injecting the immunoconjugate (IC) or free PS intraperitoneally and sacrificing the animals at 3, 6, 12, 24, 48, 72 and 168 h later. The PS was quantitated by extraction and fluorescence spectroscopy. For both the IC and free PS, peak tumour concentrations were reached at 24 h; however, the absolute concentrations for the IC were always higher (2- to 3-fold) than the free PS. Tumour to non-tumour ratios at 24 h for the IC were 6.8 for blood, 6.5 for liver, 7.2 for kidney, 5.7 for skin and 3.5 for intestine. Evaluation of viable tumour cells in ascites following in vivo PDT with a single light exposure demonstrated a dose-dependent relationship with fluence and IC concentration. However, there was significant treatment-related toxicity at all fluences. With multiple low-dose treatments, the percentage of viable tumour cells was also significantly reduced and there were no treatment-related deaths. These data suggest that, while photoimmunotherapy remains promising as a new treatment modality for ovarian cancers, careful quantitative dosimetry of both IC and light may need to be combined with multiple treatments (as with radiation therapy and chemotherapy) to control malignant disease yet maintain acceptable toxicity in vivo.