Lin X, Zhang Q, Rice J R, Stewart D R, Nowotnik D P, Howell S B
Department of Medicine and the Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0058, USA.
Eur J Cancer. 2004 Jan;40(2):291-7. doi: 10.1016/j.ejca.2003.09.022.
AP5280 is a novel N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound platinum (Pt) therapeutic designed to increase the therapeutic index relative to conventional, small-molecule platinum agents. The platinum-polymer construct accumulates in solid tumours on the basis of increased capillary permeability. The bound platinum moiety is present as an N,O-Pt chelate at the distal end of a tetrapeptide linker, glycine-phenylalanine-leucine-glycine, and the weight-average molecular weight (Mw) of the construct is 22 kDa. The antitumour activity and toxicity of AP5280 were assessed in the syngeneic murine B16F10 and Lewis lung tumour models, and in the human ovarian carcinoma 2008 and head and neck squamous carcinoma UMSCC10b xenograft models. The maximum tolerated dose (MTD) of AP5280 was 6-fold greater than that of carboplatin (CBDCA) in vivo. AP5280 was active in all four tumour models, and it displayed a higher therapeutic index than CBDCA in each of these tumour models. The antitumour effect of AP5280 given at 16% of its MTD was equivalent to that produced by a MTD of CBDCA. Thus, consistent with the design goal for this drug, and despite being less potent than CBDCA, AP5280 produced less systemic toxicity relative to its antitumour activity and thus has a greater therapeutic index. On the basis of the improved therapeutic index evidenced in these models, AP5280 has been advanced into clinical trials.
AP5280是一种新型的与N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物结合的铂（Pt）治疗药物，旨在相对于传统小分子铂类药物提高治疗指数。基于毛细血管通透性增加，铂-聚合物构建体在实体瘤中蓄积。结合的铂部分以N,O-铂螯合物的形式存在于四肽接头甘氨酸-苯丙氨酸-亮氨酸-甘氨酸的远端，构建体的重均分子量（Mw）为22 kDa。在同基因小鼠B16F10和Lewis肺癌模型以及人卵巢癌2008和头颈部鳞状癌UMSCC10b异种移植模型中评估了AP5280的抗肿瘤活性和毒性。在体内，AP5280的最大耐受剂量（MTD）比卡铂（CBDCA）高6倍。AP5280在所有四种肿瘤模型中均具有活性，并且在每个肿瘤模型中均显示出比CBDCA更高的治疗指数。以其MTD的16%给予AP5280产生的抗肿瘤效果与CBDCA的MTD产生的效果相当。因此，与该药物的设计目标一致，尽管AP5280的效力低于CBDCA，但其相对于抗肿瘤活性产生的全身毒性较小，因此具有更高的治疗指数。基于这些模型中证明的治疗指数的提高，AP5280已进入临床试验。
