This invention relates to a novel method for the delivery of cytotoxic drugs to tumor cells by the administration of a tumor-specific antibody-enzyme conjugate that binds to the tumor cells, and the additional administration of a prodrug that is converted at the tumor site, in the presence of the antibody-bound enzyme, to an active cytotoxic drug. According to preferred embodiments of this invention, antibody-enzyme conjugates containing the enzyme, alkaline phosphatase ("AP"), have been used in conjunction with the novel prodrug, etoposide-4′-phosphate or 7-(2′-aminoethyl phosphate)mitomycin or a combination thereof, to effect killing of tumor cells. According to another embodiment of the invention, an antibody-enzyme conjugate containing the enzyme, penicillin V amidase ("PVA"), has been used. in conjunction with a novel prodrug, N-(p-hydroxyphenoxyacetyl)adriamycin to effect killing of tumor cells. Still another embodiment of the invention relates to the use of an antibody-enzyme conjugate containing the enzyme, cytosine deaminase ("CD"), in combination with the prodrug, 5-fluorocytosine, to effect killing of tumor cells. The methods, antibody-enzyme conjugates, prodrugs, pharmaceutical compositions and combinations of this invention provide for enhanced selective killing of tumor cells and are thus useful in the treatment of cancers and other tumors.
本发明涉及一种向肿瘤细胞输送细胞毒性药物的新方法,该方法是通过施用能与肿瘤细胞结合的肿瘤特异性
抗体-酶结合物,并额外施用一种原药,该原药在肿瘤部位,在
抗体结合酶的存在下,转化为活性细胞毒性药物。根据本发明的优选实施方案,含有碱性
磷酸酶("AP")的
抗体-酶结合物与新型原药
依托泊苷-4′-
磷酸或 7-(2′-
氨基
乙基磷酸)丝
裂霉素或它们的复合物一起使用,可杀死肿瘤细胞。根据本发明的另一个实施方案,一种含有
青霉素 V
氨基酶("PVA")的
抗体-酶结合物与一种新型原药 N-(对羟基苯氧乙酰)
阿霉素结合使用,可杀死肿瘤细胞。本发明的另一个实施方案涉及使用含有
胞嘧啶脱
氨酶("CD")的
抗体-酶结合物与原药 5-
氟胞嘧啶结合来杀死肿瘤细胞。本发明的方法、
抗体-酶结合物、原药、药物组合物和组合物可增强对肿瘤细胞的选择性杀伤,因此可用于癌症和其他肿瘤的治疗。