Chang S G, Jung J C, Rho Y S, Huh J S, Kim J I, Hoffman R M
Department of Urology, School of Medicine, Kyung Hee University Seoul, Korea.
Anticancer Res. 1996 Nov-Dec;16(6B):3423-8.
Cisplatinum is currently used as a front line agent in many important tumors, but its dose-limiting nephrotoxicity prevents potential efficacy. There is therefore great interest in developing new platinum agents that have less toxicity. We have synthesized new platinum analogues containing DACH as a carrier ligand and DPPE as a leaving group. Previously we showed that these new platinum complexes have much less nephrotoxicity than cisplatinum. In the present study, the efficacy of one new platinum complex was evaluated with human patient bladder tumor specimens in three-dimensional histoculture as well as with monolayer cultures of cancer cell lines. The efficacy end points used were glucose consumption and thymidine incorporation on the histocultured specimens and MTT reduction on monolayer cell cultures. Our results showed that the new platinum complex was more effective at high concentration (10(-3) M) but less effective at low concentration (10(-4) M) compared to cisplatinum on histocultured bladder tumor specimens. The compound demonstrated higher efficacy than cisplatinum on P-388, and L-1210 leukemic cell lines. The new analog demonstrated similar efficacy to cisplatinum on the MKN-45 human stomach cancer cell line. The PC-14 human lung cancer cell line, MH1C1 rat hepatoma cell line, NIH-OV3, SKOV-3 ovarian cancer cell lines were as sensitive to the new analog as to cisplatinum at high concentrations of the new platinum analogue. The cisplatinum-resistant M-14 melanoma cell line was not sensitive to either the new analog or cisplatinum. Based on these results, this novel platinum compound appears to be a valuable lead compound with high efficacy and low nephrotoxicity.
顺铂目前在许多重要肿瘤中用作一线药物，但它的剂量限制性肾毒性阻碍了其潜在疗效的发挥。因此，人们对开发毒性较小的新型铂类药物有着浓厚的兴趣。我们合成了以二氨基环己烷（DACH）作为载体配体、二苯基膦乙胺（DPPE）作为离去基团的新型铂类似物。此前我们表明，这些新型铂配合物的肾毒性比顺铂小得多。在本研究中，我们使用人膀胱肿瘤标本在三维组织培养以及癌细胞系的单层培养中评估了一种新型铂配合物的疗效。所使用的疗效终点指标在组织培养标本上为葡萄糖消耗和胸苷掺入，在单层细胞培养上为MTT还原。我们的结果表明，与顺铂相比，这种新型铂配合物在高浓度（10⁻³ M）时对组织培养的膀胱肿瘤标本更有效，但在低浓度（10⁻⁴ M）时效果较差。该化合物在P - 388和L - 1210白血病细胞系上表现出比顺铂更高的疗效。这种新型类似物在MKN - 45人胃癌细胞系上表现出与顺铂相似的疗效。在新型铂类似物高浓度时，PC - 14人肺癌细胞系、MH1C1大鼠肝癌细胞系、NIH - OV3和SKOV - 3卵巢癌细胞系对这种新型类似物和顺铂的敏感性相同。耐顺铂的M - 14黑色素瘤细胞系对这种新型类似物和顺铂均不敏感。基于这些结果，这种新型铂化合物似乎是一种具有高效和低肾毒性的有价值的先导化合物。
