Senter P D, Schreiber G J, Hirschberg D L, Ashe S A, Hellström K E, Hellström I
Oncogen, Seattle, Washington 98121.
Cancer Res. 1989 Nov 1;49(21):5789-92.
Alkaline phosphatase (AP) was covalently linked to the two antitumor monoclonal antibodies, L6 (anticarcinoma) and 1F5 (anti-B lymphoma), forming conjugates that could bind to antigen-positive tumor cells. The conjugates were able to convert the prodrugs, mitomycin phosphate (MOP) and etoposide phosphate (EP), into an active mitomycin C derivative, mitomycin alcohol, and etoposide, respectively. MOP and EP were less toxic to cultured cells from the H2981 lung adenocarcinoma than their respective hydrolysis products, mitomycin alcohol and etoposide, by a factor greater than 100, and they were also less toxic in mice. Pretreatment of H2981 cells with L6-AP greatly enhanced the cytotoxic effects of MOP and EP, while 1F5-AP caused no such enhancement. A strong antitumor response was observed in H2981-bearing mice that were treated with L6-AP followed 24 h later by either MOP or a combination of MOP and EP. This response was superior to that of MOP or combinations of MOP and EP given alone.
碱性磷酸酶（AP）与两种抗肿瘤单克隆抗体L6（抗癌）和1F5（抗B淋巴瘤）共价连接，形成可与抗原阳性肿瘤细胞结合的缀合物。这些缀合物能够分别将前药丝裂霉素磷酸盐（MOP）和依托泊苷磷酸盐（EP）转化为活性丝裂霉素C衍生物丝裂霉素醇和依托泊苷。MOP和EP对H2981肺腺癌细胞的毒性比其各自的水解产物丝裂霉素醇和依托泊苷低100倍以上，并且它们对小鼠的毒性也较小。用L6-AP预处理H2981细胞可大大增强MOP和EP的细胞毒性作用，而1F5-AP则无此增强作用。在用L6-AP处理24小时后再用MOP或MOP与EP的组合处理的荷H2981小鼠中观察到强烈的抗肿瘤反应。这种反应优于单独给予MOP或MOP与EP的组合。
