Hersh E M, Gschwind C R, Taylor C W, Dorr R T, Taetle R, Salmon S E
Section of Hematology and Oncology, Arizona Cancer Center, Tucson 85724.
J Natl Cancer Inst. 1992 Aug 19;84(16):1238-44. doi: 10.1093/jnci/84.16.1238.
Imexon, a 2-cyanoaziridine, is therapeutic and reverses lymphadenopathy and splenomegaly in the LP-BM5 murine retrovirus-induced immunodeficiency disease (murine AIDS). It can restore chemotherapy-induced immunosuppression. Imexon reduced the incidence of lymphoma in severe combined immune deficient mice inoculated with human lymphocytes.
To determine its antitumor activity, we screened imexon against fresh human tumor cells and tumor cell lines. To determine the time-concentration relationships of its cytotoxicity, we studied the effects of imexon on macromolecular synthesis and on the cell cycle.
Imexon was incubated at 1-200 micrograms/mL with various tumor cell lines, mitogen-stimulated peripheral blood lymphocytes, and fresh tumor cells. Cell survival, macromolecular synthesis, and cell cycle progression were studied.
The concentration of imexon that caused 50% inhibition of growth was under 10 micrograms/mL for lymphocytes stimulated with mitogens. It was about 3-10 micrograms/mL for B-cell lymphomas and both multi-drug-resistant and -sensitive myeloma cell lines. Imexon inhibited four of seven fresh lymphoma and 11 of 16 fresh myeloma biopsy specimens to less than 40% of the control. A 1-hour exposure of lymphoma cells to 50-100 microgram/mL followed by removal of drug by washing the cells and continuing culture resulted in greater than 95% inhibition during the next 48-72 hours. Imexon selectively inhibited protein synthesis during the first 24-48 hours of exposure of lymphoma and myeloma cells. Cells exposed to inhibitory concentrations of imexon were blocked in cell cycle progression.
Imexon may be a potentially useful agent in the treatment of malignant disease, particularly lymphoid malignancies, and should be explored further.
艾美克生（Imexon）是一种2-氰基氮丙啶，具有治疗作用，可逆转LP-BM5鼠逆转录病毒诱导的免疫缺陷疾病（鼠艾滋病）中的淋巴结病和脾肿大。它可以恢复化疗引起的免疫抑制。艾美克生还降低了接种人淋巴细胞的严重联合免疫缺陷小鼠淋巴瘤的发病率。
为了确定其抗肿瘤活性，我们用艾美克生筛选了新鲜人肿瘤细胞和肿瘤细胞系。为了确定其细胞毒性的时间-浓度关系，我们研究了艾美克生对大分子合成和细胞周期的影响。
将艾美克生以1 - 200微克/毫升的浓度与各种肿瘤细胞系、丝裂原刺激的外周血淋巴细胞和新鲜肿瘤细胞一起孵育。研究细胞存活、大分子合成和细胞周期进程。
对于丝裂原刺激的淋巴细胞，引起50%生长抑制的艾美克生浓度低于10微克/毫升。对于B细胞淋巴瘤以及多药耐药和敏感的骨髓瘤细胞系，该浓度约为3 - 10微克/毫升。艾美克生将7份新鲜淋巴瘤活检标本中的4份以及16份新鲜骨髓瘤活检标本中的11份抑制至对照的40%以下。淋巴瘤细胞暴露于50 - 100微克/毫升的艾美克生1小时，然后通过洗涤细胞去除药物并继续培养，在接下来的48 - 72小时内抑制率大于95%。艾美克生在淋巴瘤和骨髓瘤细胞暴露的最初24 - 48小时内选择性抑制蛋白质合成。暴露于抑制浓度艾美克生的细胞在细胞周期进程中被阻断。
艾美克生可能是治疗恶性疾病，特别是淋巴恶性肿瘤的一种潜在有用药物，应进一步探索。
