Goff B A, Hermanto U, Rumbaugh J, Blake J, Bamberg M, Hasan T
Vincent Gynecology Service, Massachusetts General Hospital, Harvard Medical School, Boston 02114.
Br J Cancer. 1994 Sep;70(3):474-80. doi: 10.1038/bjc.1994.330.
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.
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（PSs）会被适当波长的光激活。通过将PSs与载体大分子如单克隆抗体（MAbs）连接，可以提高其靶向特异性。OC125是一种鼠源单克隆抗体，可识别抗原CA 125，80%的非黏液性卵巢肿瘤均表达该抗原。与OC125偶联的二氢卟吩衍生物在体外和离体实验中对卵巢癌及其他CA 125阳性细胞具有选择性光毒性。我们现在报告使用腹水型Balb/c裸鼠卵巢癌模型进行的体内研究。通过腹腔注射人卵巢癌细胞系NIH:OVCAR3的细胞诱导产生腹水。注射六周后，当动物出现腹水时，通过腹腔注射免疫缀合物（IC）或游离PS进行生物分布研究，并在3、6、12、24、48、72和168小时后处死动物。通过萃取和荧光光谱法定量PS。对于IC和游离PS，肿瘤浓度峰值均在24小时达到；然而，IC的绝对浓度始终高于游离PS（2至3倍）。IC在24小时时的肿瘤与非肿瘤组织的比值，血液为6.8，肝脏为6.5，肾脏为7.2，皮肤为5.7，肠道为3.5。单次光暴露体内PDT后腹水活肿瘤细胞的评估显示，其与光通量和IC浓度呈剂量依赖关系。然而，在所有光通量下均存在显著的治疗相关毒性。采用多次低剂量治疗时，活肿瘤细胞百分比也显著降低，且无治疗相关死亡。这些数据表明，虽然光免疫疗法作为卵巢癌的一种新治疗方式仍具有前景，但可能需要仔细对IC和光进行定量剂量测定，并结合多次治疗（如同放疗和化疗），以控制恶性疾病并在体内维持可接受的毒性。
