Comparative efficacy of novel platinum(IV) compounds with established chemotherapeutic drugs in solid tumour models
Comparative efficacy of novel platinum(IV) compounds with established chemotherapeutic drugs in solid tumour models
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DOI：
10.1016/j.bcp.2003.07.016
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发表时间：
2004-01-01
影响因子：
5.8
通讯作者：
Callaghan, R
中科院分区：
文献类型：
--
作者：
Hall, MD;Martin, C;Callaghan, R
以铂(H)为基础的抗癌药物反应性高，生物稳定性差。铂(IV)配合物由于其更大的稳定性和生物还原活性而显示出潜在的优势，从而允许更大比例的药物完好无损地到达目标位置。所有被测试的化合物都能在单层细胞培养中产生细胞毒性，然而，铂(IV)药物的效力低于铂(H)化合物或现有的有机化疗药物。与单层培养相比，铂(II)或(IV)化合物在多细胞肿瘤球体(MCTS)中产生细胞毒性的效力没有显著变化。所有有机和铂基细胞毒剂都不同程度地抑制或减少了MCTS的生长。在中层(d=350um)和大层(d=600um)MCT中，增殖细胞局限于外层2~3个细胞层。不管MCTS的大小，药物治疗产生了更大和更广泛分布的增殖细胞群，这与细胞毒损伤后静止细胞重新聚集到增殖池中是一致的。组织学检查表明，虽然存在药物依赖效应，如长春花碱引起的中期分裂停滞和阿霉素引起的染色质弥散到细胞核的边缘，但其主要的形态改变是细胞凋亡。总而言之，虽然铂(IV)衍生物能够通过细胞凋亡产生细胞毒性，但引入稳定的轴基显著减缓了这种情况发生的速度。(C)2003 Elsevier Inc.保留所有权利。
Platinum(H)-based anticancer drugs are associated with high reactivity and thus a poor biological stability. The platinum(IV)complexes display potential advantages due to their greater stability and bioreductive activation, thereby allowing a greater proportion of the drug to arrive at the target intact. All compounds tested were able to produce cytotoxicity in monolayer cell cultures, however, the potencies of platinum(IV) drugs were lower than that observed for the platinum(H) compounds or established organic chemotherapeutic agents. There was no significant alteration in the potency of platinum(II) or (IV) compounds to produce cytotoxicity in multicellular tumour spheroids (MCTS) compared to monolayer cultures. All the organic and platinum-based cytotoxic agents produced, to varying degrees, either a retardation or reduction in MCTS growth. Proliferating cells were restricted to the outer two to three cellular layers in intermediate (d = 350 mum) and large (d = 600 mum) MCTS. Regardless of MCTS size, drug treatment produced a larger and more widely distributed proliferating cell population, consistent with the recruitment of quiescent cells to the proliferating pool following cytotoxic damage. Histology indicated that the predominant morphological change was that of apoptosis, although there was some drug-dependent effects such as the metaphase arrest produced by vinblastine and chromatin dispersal to the periphery of nuclei produced by doxorubicin. In summary, whilst the platinum(IV) derivatives were able to produce cytotoxicity via apoptosis, the introduction of a stable axial group significantly retarded the rate at which this occurred. (C) 2003 Elsevier Inc. All rights reserved.