基于新发现作用机制的新型抗肿瘤抗生素研究

Gan To Kagaku Ryoho. 1983 Apr;10(4 Pt 2):1094-106.

In our laboratory, we have studied the mechanism of action of tumor-inhibitory antibiotics, including bleomycin, phleomycin, adriamycin, aclarubicin, neothramycin, macromomycin, auromomycin, chartreusin, pluramycin, neopluramycin, xanthomycin A, angustmycins A and C, blasticidin S and phenomycin. The recent advances are summarized. Screening of microorganism for new antitumor antibiotics based upon our studies on mechanism of action are currently ongoing. We are interested in drug-resistance of tumor cells, and have obtained drug-resistant sublines of murine lymphoblastoma L5178Y cells. We have found that glycoprotein synthesis and alkaline phosphodiesterase (APD) activity of the plasma membrane are higher in adriamycin (ADM)-, aclarubicin (ACR)- and bleomycin (BLM)-resistant cell sublines than in the parental cells. An inhibitor of APD has been isolated from a soil Streptomyces, and identified with 2-crotonyloxymethyl-4,5,6-trihydroxycyclohex-2-enone (COTC). COTC inhibits growth of the drug-resistant cells more significantly than the parental cells, and exhibits synergistic activity with ACR against ACR-resistant cells. COTC is a SH inhibitor. Although COTC is a multifunctional drug, the inhibition of DNA polymerase alpha and some mitotic process may be related to its lethal action. In the course of our screening, we have found that a strain of Sterptomyces hygroscopicus produces two substances: one inhibits thymidine and uridine uptake of human leukemic K562 cells, and the other stimulates it. The inhibiting substance has been identified with tubercidin, and the stimulating one has been found to be a novel pyrrolo [2,3-d] pyrimidine antibiotic, cadeguomycin. Cadeguomycin shows low acute toxicity in mice, enhances DTH reaction, and inhibits Ehrlich ascitic carcinoma in mice. The antibiotic exhibits synergistic effects with arabinosylcytosine against growth of K562 cells. Saframycin, discovered by Prof. Arai, Chiba University, is effective against Ehrlich ascitic carcinoma, P388 and L1210 leukemia, and B16 melanoma in mice. The target is DNA. Stubomycin, discovered by Dr. Umezawa, Kitasato Institute, is effective against Sarcoma 180, Ehrlich carcinoma, P388 leukemia, IMC carcinoma and Meth-A tumor in mice, and shows low acute toxicity. The target is plasma membrane.

在我们实验室，我们研究了包括博来霉素、腐草霉素、阿霉素、阿柔比星、新制癌菌素、大霉素、金霉素、黄绿青霉素、腐霉素、新腐霉素、黄原霉素A、安古霉素A和C、杀稻瘟菌素S和表霉素在内的肿瘤抑制性抗生素的作用机制。现将近期进展进行总结。基于我们对作用机制的研究，目前正在筛选新的抗肿瘤抗生素的微生物。我们对肿瘤细胞的耐药性感兴趣，并已获得小鼠淋巴瘤L5178Y细胞的耐药亚系。我们发现，阿霉素（ADM）、阿柔比星（ACR）和博来霉素（BLM）耐药细胞亚系的糖蛋白合成和质膜碱性磷酸二酯酶（APD）活性高于亲代细胞。已从土壤链霉菌中分离出一种APD抑制剂，并鉴定为2-巴豆酰氧基甲基-4,5,6-三羟基环己-2-烯酮（COTC）。COTC对耐药细胞生长的抑制作用比对亲代细胞更显著，并与ACR对ACR耐药细胞表现出协同活性。COTC是一种巯基抑制剂。尽管COTC是一种多功能药物，但其对DNA聚合酶α和某些有丝分裂过程的抑制作用可能与其致死作用有关。在我们的筛选过程中，我们发现一株吸水链霉菌产生两种物质：一种抑制人白血病K562细胞对胸苷和尿苷的摄取，另一种则刺激其摄取。抑制物质已鉴定为杀结核菌素，刺激物质被发现是一种新型吡咯并[2,3-d]嘧啶抗生素，卡德古霉素。卡德古霉素在小鼠中显示出低急性毒性，增强迟发型超敏反应，并抑制小鼠艾氏腹水癌。该抗生素与阿糖胞苷对K562细胞生长表现出协同作用。由千叶大学的新井教授发现的沙弗拉霉素对小鼠艾氏腹水癌、P388和L1210白血病以及B16黑色素瘤有效。作用靶点是DNA。由北里研究所的梅泽博士发现的施托布霉素对小鼠肉瘤180、艾氏癌、P388白血病、IMC癌和Meth-A肿瘤有效，并显示出低急性毒性。作用靶点是质膜。