Galeano A, Berger M R, Keppler B K
Institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg.
Cancer Chemother Pharmacol. 1992;30(2):131-8. doi: 10.1007/BF00686405.
Two new platinum-containing phosphonate compounds, cis-diammine[nitrilotris(methylphosphonato)(2-)- O1,N1]platinum(II) (AMDP) and cis-cyclohexane-1,2-diamine[nitrilotris(methylphosphonato) (2-)-O1,N1]platinum(II) (DADP) were investigated in acetoxy-methyl-methylnitrosamine-induced autochthonous colorectal rat adenocarcinoma in vivo as well as in two human colon-cancer cell lines (SW707 and SW948) in vitro. In the in vivo model, the two compounds were given i.v. at doses of 8 and 13 mg/kg as well as p.o. at 16 and 26 mg/kg twice a week for 10 weeks, respectively. AMDP produced more intensive toxicity at both doses but showed higher antitumour activity only following i.v. administration. On the other hand, DADP caused significant tumour-growth inhibition after both modes of application, but as it produced only low toxicity, its use should be favoured. The in vitro assays were performed using two cell lines derived from human colorectal adenocarcinomas. According to the microculture tetrazolium test (MTT) AMDP (IC50, 34 and 59 microM in SW707 and SW948, respectively) was more effective than DADP (IC50, 412 and 660 microM in SW707 and SW948, respectively) in inhibiting cell growth. Based on cell counts AMDP (IC50, 8 and 11 microM in SW707 and SW948, respectively) and DADP (IC50, 266 and 285 microM in SW707 and SW948, respectively) showed more intensive antiproliferative efficacy as determined by the Coulter Counter method vs the MTT assay. The promising activities of these new platinum-linked phosphonic acids in autochthonous rat colorectal carcinoma and in human colorectal cancer cell lines warrant further investigations of compounds of this class to elucidate their role in the treatment of colorectal cancer.
研究了两种新型含铂膦酸盐化合物，顺式二胺[次氮基三(甲基膦酸根)(2 -)-O1,N1]铂(II)(AMDP)和顺式环己烷-1,2 -二胺[次氮基三(甲基膦酸根)(2 -)-O1,N1]铂(II)(DADP)，在体内对乙氧甲基甲基亚硝胺诱导的大鼠自发性结直肠癌的作用，以及在体外对两种人结肠癌细胞系(SW707和SW948)的作用。在体内模型中，两种化合物分别以8和13 mg/kg的剂量静脉注射，以及以16和26 mg/kg的剂量口服给药，每周两次，共10周。两种剂量下，AMDP的毒性更强，但仅在静脉注射给药后显示出更高的抗肿瘤活性。另一方面，DADP在两种给药方式后均引起显著的肿瘤生长抑制，且因其毒性较低，应优先使用。体外试验使用了两种源自人结肠腺癌的细胞系。根据微量培养四唑盐试验(MTT)，AMDP(在SW707和SW948中的IC50分别为34和59 microM)在抑制细胞生长方面比DADP(在SW707和SW948中的IC50分别为412和660 microM)更有效。基于细胞计数，与MTT试验相比，通过库尔特计数器法测定，AMDP(在SW707和SW948中的IC50分别为8和11 microM)和DADP(在SW707和SW948中的IC50分别为266和285 microM)显示出更强的抗增殖效果。这些新型铂连接膦酸在大鼠自发性结直肠癌和人结肠癌细胞系中的有前景的活性，值得对这类化合物进行进一步研究，以阐明它们在结直肠癌治疗中的作用。
