A water soluble prodrug of a novel camptothecin analog is efficacious against breast cancer resistance protein-expressing tumor xenografts
A water soluble prodrug of a novel camptothecin analog is efficacious against breast cancer resistance protein-expressing tumor xenografts
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DOI：
10.1007/s00280-009-1042-5
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发表时间：
2010-01-01
影响因子：
3
通讯作者：
Yamada-Okabe, Hisafumi
中科院分区：
文献类型：
--
作者：
Endo, Mika;Miwa, Masanori;Yamada-Okabe, Hisafumi
一种新的拓扑异构酶I抑制剂的鉴定显示出比盐酸伊立替康（CPT-11）更好的上级疗效和更小的个体差异。筛选了一种新的对乳腺癌耐药蛋白（BCRP）阳性细胞有效的喜树碱类似物，并产生了一种水溶性前药。在BCRP阳性和阴性的异种移植瘤中检测了前体药物单独使用以及与其他抗癌药物联合使用的抗肿瘤活性，发现了一种新的喜树碱类似物CH 0793076。因为发现CH 0793076是高度亲脂性的，所以产生了水溶性前药（TP 300）。TP 300在酸性溶液中稳定，但在生理pH条件下（如血清中）迅速转化为CH 0793076。这种有效的前药活化将使药代动力学和毒性特征的患者间差异最小化。与CPT-11不同，TP 300在有效剂量下不会表现出胆碱能相互作用或引起急性腹泻。在小鼠异种移植模型中，TP 300对BCRP阳性和阴性异种移植物均显示出抗肿瘤活性，而CPT-11对BCRP阳性异种移植物的活性较低。此外，TP 300的有效剂量范围（MTD/ED 50）比CPT-11更宽，TP 300与其他抗癌药物如卡培他滨、奥沙利铂、顺铂、贝伐珠单抗和西妥昔单抗联合使用时显示出相加或协同的抗肿瘤作用，因此预期TP 300将为将接受喜树碱类化疗的患者提供额外的治疗选择。
Identification of a novel topoisomerase I inhibitor which shows superior efficacy and less individual variation than irinotecan hydrochloride (CPT-11).A novel camptothecin analog that is effective against breast cancer resistance protein (BCRP)-positive cells was screened, and a water soluble prodrug was generated. Antitumor activity of the prodrug was examined in BCRP-positive and -negative xenografts both as a single agent and in combination with other anti-cancer drugs.A novel camptothecin analog, CH0793076, was discovered. Because CH0793076 was found to be highly lipophilic, a water soluble prodrug (TP300) was generated. TP300 is stable in an acidic solution but is rapidly converted to CH0793076 under physiological pH conditions such as in sera. This efficient prodrug activation would minimize interpatient differences in pharmacokinetic and toxicity profiles. Unlike CPT-11, TP300 does not exhibit cholinergic interaction or cause acute diarrhea at effective doses. In mouse xenograft models, TP300 showed antitumor activity against both BCRP-positive and -negative xenografts, whereas CPT-11 was less active against BCRP-positive xenografts. In addition, the effective dose range (MTD/ED50) for TP300 was wider than for CPT-11 and TP300 showed additive or synergistic antitumor effects in combination with other anti-cancer drugs such as capecitabine, oxaliplatin, cisplatin, bevacizumab and cetuximab.It is therefore expected that TP300 will provide an additional treatment option for patients who will undergo chemotherapy with camptothecins.