Marks A, Ettenson D, Bjorn M J, Lei M, Baumal R
Banting and Best Department of Medical Research, University of Toronto, Ontario, Canada.
Cancer Res. 1990 Jan 15;50(2):288-92.
Intracavitary administration of immunotoxins may play a role in the control of malignant effusions. Selection of immunotoxins for this form of therapy is based on their prior evaluation in preclinical studies. Monoclonal antibodies (mAb) 454A12 (antitransferrin receptor), and 260F9 are directed against antigens which are present on tumor cells in pleural and peritoneal effusions of patients with adenocarcinoma of the breast and ovary. In the present study, immunotoxins derived by conjugating these mAb to recombinant ricin A (rRA) were shown to be cytotoxic to human ovarian adenocarcinoma HEY cells in vitro and in vivo. In the in vitro assay 454A12-rRA and 260F9-rRA were 1000-fold and 10-fold, respectively, more cytotoxic than free rRa against HEY cells, and both immunotoxins were potentiated approximately 1000-fold by monensin. For in vivo studies HEY cells were injected i.p. into nude mice at a challenge dose (3 x 10(5) cells) which produced carcinomatosis with ascites, leading to death 30 days following injection. Administration of 454A12-rRA i.p. following the challenge dose resulted in a complete cure, whereas administration of 260 F9-rRA with monensin significantly prolonged survival. The greater cytotoxicity of 454A12-rRA than 260F9-rRA against HEY cells could be accounted for by the greater number of binding sites and higher internalization rate for 454A12-rRA and mAb 454A12 than 260F9-rRA and mAb 260F9, respectively. These results suggest a potential role for 454A12-rRA and 260F9-rRA plus monensin in the intracavitary therapy of malignant effusions associated with carcinoma of breast and ovary. In the case of 260F9-rRA, this represents the first preliminary indication of the suitability of this immunotoxin for intracavitary therapy of malignancies.
腔内注射免疫毒素可能在控制恶性积液方面发挥作用。选择用于这种治疗形式的免疫毒素是基于它们在临床前研究中的预先评估。单克隆抗体（mAb）454A12（抗转铁蛋白受体）和260F9针对的抗原存在于乳腺癌和卵巢癌患者胸腔和腹腔积液中的肿瘤细胞上。在本研究中，通过将这些单克隆抗体与重组蓖麻毒素A（rRA）偶联得到的免疫毒素在体外和体内均显示对人卵巢腺癌HEY细胞具有细胞毒性。在体外试验中，454A12-rRA和260F9-rRA对HEY细胞的细胞毒性分别比游离rRa高1000倍和10倍，并且两种免疫毒素均被莫能菌素增强约1000倍。在体内研究中，将HEY细胞以激发剂量（3×10⁵个细胞）腹腔注射到裸鼠中，该剂量会导致癌性腹水，注射后30天导致死亡。在激发剂量后腹腔注射454A12-rRA可实现完全治愈，而联合莫能菌素注射260F9-rRA可显著延长生存期。454A12-rRA对HEY细胞的细胞毒性大于260F9-rRA，这可能分别是由于454A12-rRA和单克隆抗体454A12比260F9-rRA和单克隆抗体260F9具有更多的结合位点和更高的内化率。这些结果表明454A12-rRA和260F9-rRA加莫能菌素在与乳腺癌和卵巢癌相关的恶性积液腔内治疗中具有潜在作用。就260F9-rRA而言，这代表了这种免疫毒素适用于恶性肿瘤腔内治疗的首个初步迹象。
