Teicher B A, Herman T S, Pfeffer M R, Alvarez Sotomayor E, Khandekar V S
Dana-Farber Cancer Institute, Boston, Massachusetts.
Cancer Res. 1989 Nov 15;49(22):6208-13.
We are developing complexes of negatively charged PtCl4 with positively charged nuclear dyes as new antitumor agents for use alone and in conjunction with hyperthermia and/or radiation. Elemental analysis has shown that the complex PtCl4(Fast Black)2 is a tight ion pair. In experimentally growing EMT6 cells in vitro, PtCl4(Fast Black)2 killed cells in a log-linear manner which increased as the temperature of the exposures was increased from 37 to 42 degrees C or 43 degrees C. In addition, cell kill was also increased under conditions of low pH (6.45), especially in hypoxic cells treated at elevated temperature. Measurement of intracellular platinum levels after exposure to 25 microM cisplatin or PtCl4(Fast Black)2 demonstrated that platinum levels were between 170- and 200-fold higher after exposure to PtCl4(Fast Black)2. In vivo studies in the FSaIIC murine fibrosarcoma showed, again, that PtCl4(Fast Black)2 killed in a log-linear manner. Treatment of tumors placed in the thigh with 43 degrees C, 30-min hyperthermia immediately following i.p. injection of PtCl4(Fast Black)2 was dose modifying. One hundred mg/kg of PtCl4(Fast Black)2 produced a 4.6-day tumor growth delay which increased to 6.4 days with 43 degrees C, 30-min hyperthermia immediately following i.p. injection of PtCl4(Fast Black)2 was does modifying. One hundred mg/kg of PtCl4(Fast Black)2 produced a 4.6-day tumor growth delay which increased to 6.4 days with 43 degrees C, 30-min hyperthermia (growth delay for hyperthermia alone was 1.4 days), and 500 mg/kg produced a 5.6-day delay which increased to 11.0 days with hyperthermia. In contrast, cisplatin (5 mg/kg) produced a 4.4-day delay which increased to 5.9 days with hyperthermia. PtCl4(Fast Black)2 was well tolerated by animals, and the maximally tolerated dose was approximately 650 mg/kg. This new complex appears quite active as an antitumor agent alone and in conjunction with hyperthermia, and, since other studies have shown it to interact positively with radiation, this agent seems a very appropriate candidate for further development as a clinical anticancer drug.
我们正在研发带负电荷的PtCl4与带正电荷的核染料的复合物，将其作为新型抗肿瘤药物，可单独使用，也可与热疗和/或放疗联合使用。元素分析表明，复合物PtCl4（固绿）2是一种紧密离子对。在体外培养的EMT6细胞实验中，PtCl4（固绿）2以对数线性方式杀死细胞，随着暴露温度从37℃升高到42℃或43℃，细胞杀伤作用增强。此外，在低pH（6.45）条件下细胞杀伤作用也增强，尤其是在高温处理的缺氧细胞中。暴露于25μM顺铂或PtCl4（固绿）2后测量细胞内铂含量表明，暴露于PtCl4（固绿）2后铂含量高出170至200倍。在FSaIIC小鼠纤维肉瘤的体内研究中，再次表明PtCl4（固绿）2以对数线性方式杀死肿瘤细胞。腹腔注射PtCl4（固绿）2后立即用43℃、30分钟的热疗处理大腿处的肿瘤具有剂量修饰作用。100mg/kg的PtCl4（固绿）2使肿瘤生长延迟4.6天，腹腔注射PtCl4（固绿）2后立即用43℃、30分钟的热疗处理，肿瘤生长延迟增加到6.4天（单独热疗的生长延迟为1.4天），500mg/kg导致5.6天延迟并因热疗增加到11.0天。相比之下，顺铂（5mg/kg）导致4.4天延迟并因热疗增加到5.9天。动物对PtCl4（固绿）2耐受性良好，最大耐受剂量约为650mg/kg。这种新复合物作为单独的抗肿瘤药物以及与热疗联合使用时似乎相当有效，而且，由于其他研究表明它与放疗有积极相互作用，这种药物似乎是进一步开发为临床抗癌药物的非常合适的候选药物。
