Hidalgo M, Izbicka E, Eckhardt S G, MacDonald J R, Cerna C, Gomez L, Rowinsky E K, Weitman S D, Von Hoff D D
Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, 78229, USA.
Anticancer Drugs. 1999 Oct;10(9):837-44. doi: 10.1097/00001813-199910000-00007.
MGI 114 (6-hydroxymethylacylfulvene, HMAF) is a novel semisynthetic antitumor compound derived from the sesquiterpene mushroom toxin illudin S. Although illudins did not demonstrate significant activity as antiproliferative agents in tumor-bearing animals, several properties including its potent inhibition of DNA synthesis and a unique interaction with DNA led to a structure-activity-based synthetic effort to obtain analogs with improved therapeutic potential. MGI 114 was selected for further development based on its antitumor activity in numerous preclinical tests. MGI 114 was evaluated against adult and pediatric human tumors taken directly from cancer patients and cultured in a human tumor colony-forming assay (HTCFA) to assess the antitumor spectra, concentration-response relationship, schedule dependence and activity of this agent against tumors considered resistant to conventional anticancer drugs. Human tumor colony-forming units were treated with HMAF at concentrations of 0.001, 0.01, 0.1 and 1 microg/ml, both as a 1 h exposure and as a continuous 14 day exposure. A response was scored if there was 50% or less colony survival. In vitro response rates in the range of 50-80% were observed against tumor colony-forming units originating from carcinomas of the colon, kidney, breast, lung cancer, ovary and melanoma. MGI 114 also demonstrated antitumor activity against neuroblastoma colony-forming units. Antitumor activity was not influenced by exposure time as demonstrated by the similar responses rates obtained with the 1 h and continuous exposure at all concentrations tested. However, there was a significant positive concentration-response relationship to both exposure duration with responses increasing from below 10% at the lowest concentration to over 70% at the highest concentration, except for the pediatric tumors on the 1 h exposure for which this relationship was less apparent. At the higher concentration tested, MGI 114 displayed substantial antiproliferative effects in the range of 70% against tumor specimens resistant to classic cytotoxic agents including irinotecan, paclitaxel, 5-fluorouracil, cisplatin, doxorubicin and cyclophosphamide. These results demonstrate that MGI 114 exhibits a broad spectrum of antitumor activity against both adult and pediatric primary tumor colony-forming units in a concentration-dependent manner both at short and prolonged exposure duration. The substantial in vitro activity of MGI 114 at concentrations achievable in clinical trials, together with its activity against tumors resistant to classic standard cytotoxic drugs, justifies the further clinical evaluation of this unique agent.
MGI 114（6-羟甲基酰基富烯，HMAF）是一种新型半合成抗肿瘤化合物，源自倍半萜蘑菇毒素隐杯伞素S。尽管隐杯伞素在荷瘤动物中作为抗增殖剂未表现出显著活性，但其包括对DNA合成的强力抑制以及与DNA的独特相互作用等多种特性，促使基于构效关系进行合成研究以获得具有更高治疗潜力的类似物。基于其在众多临床前试验中的抗肿瘤活性，MGI 114被选作进一步研发。在人肿瘤集落形成试验（HTCFA）中，对直接取自癌症患者的成人和儿童人类肿瘤进行了MGI 114评估，以评估该药物的抗肿瘤谱、浓度-反应关系、给药方案依赖性以及对被认为对传统抗癌药物耐药的肿瘤的活性。用浓度为0.001、0.01、0.1和1微克/毫升的HMAF处理人肿瘤集落形成单位，处理方式包括1小时暴露和连续14天暴露。如果集落存活率为50%或更低，则判定为有反应。观察到MGI 114对源自结肠癌、肾癌、乳腺癌、肺癌、卵巢癌和黑色素瘤的肿瘤集落形成单位的体外反应率在50%至80%之间。MGI 114对神经母细胞瘤集落形成单位也显示出抗肿瘤活性。如在所有测试浓度下1小时暴露和连续暴露所获得的相似反应率所示，暴露时间不影响抗肿瘤活性。然而，存在显著的正浓度-反应关系，且与暴露持续时间有关，反应率从最低浓度下的低于10%增加到最高浓度下的超过70%，但1小时暴露的儿童肿瘤除外，其这种关系不太明显。在测试的较高浓度下，MGI 114对包括伊立替康、紫杉醇、5-氟尿嘧啶、顺铂、阿霉素和环磷酰胺在内的对经典细胞毒性药物耐药的肿瘤标本显示出70%左右的显著抗增殖作用。这些结果表明，MGI 114在短期和长期暴露时均以浓度依赖性方式对成人和儿童原发性肿瘤集落形成单位表现出广泛的抗肿瘤活性。MGI 114在临床试验可达到的浓度下具有显著的体外活性，以及其对经典标准细胞毒性药物耐药肿瘤的活性，证明了对这种独特药物进行进一步临床评估的合理性。
