Regenass U, Mett H, Stanek J, Mueller M, Kramer D, Porter C W
Research Department, CIBA-GEIGY, Basel, Switzerland.
Cancer Res. 1994 Jun 15;54(12):3210-7.
Inhibitors of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (SAMDC), derived from methylglyoxal-bis(guanylhydrazone) (MGBG), have been shown to have significant antitumor activity in several human solid tumor systems (U. Regenass et al., Cancer Res., 52:4712-4718, 1992). From an ongoing effort to synthesize derivatives with increased enzyme specificity and potency and improved antitumor efficacy, we have now identified CGP 48664, a 4-amidinoindan-1-one 2'-amidinohydrazone (J. Stanek et al., J. Med. Chem., 36:2168-2171, 1993). The compound displays potent inhibition of SAMDC (50% inhibitory concentration, 5 nM), modest inhibition of diamine oxidase (50% inhibitory concentration, 4 microM), and no detectable inhibition of ornithine decarboxylase. CGP 48664 inhibits the growth of a panel of human and mouse tumor cell lines, including one which expresses the multidrug resistance phenotype, with 50% inhibitory concentrations ranging between 0.3 and 3 microM. CGP 48664 does not seem to utilize the polyamine transport carrier system since it competes poorly with spermidine for uptake into L1210 cells (Ki 161 microM) and inhibits the growth of polyamine transport-deficient Chinese hamster ovary cells. Relative to MGBG or previously described MGBG analogues, CGP 48664 accumulates to much lower intracellular concentrations. Treatment of the L1210 cell for 48 h with 3 microM CGP 48664 decreases SAMDC activity to < 10% of control and initiates a compensatory 3-fold rise in ornithine decarboxylase. Consistent with SAMDC inhibition, putrescine pools increase 10-fold, whereas spermidine and spermine pools fall to < 10% of control. In contrast to MGBG, CGP 48664 displays attenuated antimitochondrial activity as indicated by a lack of effect on pyruvate oxidation and mitochondrial DNA levels under treatment conditions which inhibit cell proliferation. Specificity of drug action was indicated further by prevention of L1210 cell growth inhibition by exogenous spermidine or spermine. More convincingly, Chinese hamster ovary cells made approximately 1000-fold resistant by chronic exposure to the analogue were found to selectively overexpress SAMDC mRNA due to gene amplification. The new SAMDC inhibitor showed potent antitumor activity against syngeneic tumors (B16 melanoma and Lewis lung carcinoma) and nude mouse human tumor xenografts (T-24 bladder carcinoma, SK MEL-24 melanoma, and MALME-3M melanoma). On the basis of its novel structure, its apparent specificity of action, and its potent antitumor activity, CGP 48664 is the candidate drug for further preclinical development.
源自甲基乙二醛双（脒腙）（MGBG）的多胺生物合成酶S-腺苷甲硫氨酸脱羧酶（SAMDC）抑制剂，已显示在多种人类实体瘤系统中具有显著的抗肿瘤活性（U. Regenass等人，《癌症研究》，52:4712 - 4718，1992）。为了不断努力合成具有更高酶特异性、更高效力和更好抗肿瘤疗效的衍生物，我们现已鉴定出CGP 48664，一种4-脒基茚满-1-酮2'-脒基腙（J. Stanek等人，《药物化学杂志》，36:2168 - 2171，1993）。该化合物对SAMDC表现出强效抑制作用（50%抑制浓度，5 nM），对二胺氧化酶有适度抑制作用（50%抑制浓度，4 microM），对鸟氨酸脱羧酶无明显抑制作用。CGP 48664抑制一组人类和小鼠肿瘤细胞系的生长，包括一个表达多药耐药表型的细胞系，其50%抑制浓度在0.3至3 microM之间。CGP 48664似乎不利用多胺转运载体系统，因为它与亚精胺竞争进入L1210细胞的摄取能力较差（Ki 161 microM），并抑制多胺转运缺陷的中国仓鼠卵巢细胞的生长。相对于MGBG或先前描述的MGBG类似物，CGP 48664在细胞内的积累浓度要低得多。用3 microM CGP 48664处理L1210细胞48小时，可使SAMDC活性降至对照的<10%，并引发鸟氨酸脱羧酶代偿性3倍升高。与SAMDC抑制一致，腐胺池增加10倍，而亚精胺和精胺池降至对照的<10%。与MGBG不同，CGP 48664在抑制细胞增殖的处理条件下，对丙酮酸氧化和线粒体DNA水平无影响，显示出减弱的抗线粒体活性。外源亚精胺或精胺可预防L1210细胞生长抑制，进一步表明了药物作用的特异性。更有说服力的是，通过长期暴露于该类似物而产生约1000倍抗性的中国仓鼠卵巢细胞，由于基因扩增而选择性地过度表达SAMDC mRNA。这种新型SAMDC抑制剂对同基因肿瘤（B16黑色素瘤和Lewis肺癌）和裸鼠人肿瘤异种移植瘤（T - 24膀胱癌、SK MEL - 24黑色素瘤和MALME - 3M黑色素瘤）显示出强效抗肿瘤活性。基于其新颖的结构、明显独特的作用方式和强效的抗肿瘤活性，CGP 48664是进一步临床前开发的候选药物。
