真菌产生的新核苷转运抑制剂增强药物的抗肿瘤活性

从南极土壤中分离的一株真菌所产生的抗生素C3368-B(CB)有较强的核苷转运抑制活性。CB显著抑制艾氏腹水癌(EAC)细胞的胸苷和尿苷转运,IC₅₀分别为7.5和9.6μmol·L^-1。用克隆生成法测定,CB在本身无明显细胞毒性剂量下,能显著增强氨甲蝶呤(MTX)、5-氟脲嘧啶(5FU)和丝裂霉素C(MMC)等抗癌药物对人口腔鳞癌KB细胞和人肝癌BEL-7402细胞的杀伤。生长抑制法结果显示,CB还能部分逆转小鼠白血病L1210/MDR细胞对长春新碱(VCR)和放线菌素D(ACD)的抗药性。结果提示新核苷转运抑制剂CB可能应用于肿瘤联合化疗的前景。

A FUNGUS-DERIVED NOVEL NUCLEOSIDE TRANSPORT INHIBITOR POTENTIATES THE ACTIVITY OF ANTITUMOR DRUGS

Antibiotic C3368-B(CB),identified as,3,9-dihydroxy-1-methoxy-7-methylanth-raquinone ,is produced by a fungus strain ,Chrysosporium verrucosum Tubaki ,isolated from a soilsample collected from Antarctica. CB was found to be a highly-active nucleoside transport inhibitor.By radiolabelled nucleoside assay ,CB was shown to markedly inhibit thymidine and uridine transportin Ehrlich carcinoma cells , with IC₅₀ values of 7.5 and 9.6umol·L^-1 respectively,CB showedfairly low cytotoxicity to tumor cells. The IC₅₀ values for epidermoid cancer KB cells and hepatomaBEL-7402 cells in clonogenic assay was 77 and 69umol·L^-1 .At relatively noncytotoxic concentra-tions, CB markedly enhanced the cytotoxicity of methotrexate,5-fluorouracil, mitomycin C againstKB cells and BEL-7402 cells. CB was also found to partly revers1e the multi-drug resistance tovincristine and actinomvcin D in leukemia L1210/ MDR cells. The IC₅₀ values were reduced by4.9-fold(1.75 to 0.36umol·L^-1) for vincristine and 3.3-fold(0.39 to 0.12umol·L^-1) foractinomvcin D. These results suggest that CB , as a newly-found nucleoside transport inhibitor , maybe potentially useful in cancer chemotherapy.