一种新型喜树碱类似物的水溶性前药对表达乳腺癌耐药蛋白的肿瘤异种移植物有效。

A water soluble prodrug of a novel camptothecin analog is efficacious against breast cancer resistance protein-expressing tumor xenografts.

机构信息

Kamakura Research Laboratories, Pharmaceutical Research Department, Chugai Pharmaceutical Co. Ltd., Kajiwara, Kanagawa, Japan.

出版信息

Cancer Chemother Pharmacol. 2010 Jan;65(2):363-71. doi: 10.1007/s00280-009-1042-5.

DOI:10.1007/s00280-009-1042-5

PMID:19495753

Abstract

PURPOSE

Identification of a novel topoisomerase I inhibitor which shows superior efficacy and less individual variation than irinotecan hydrochloride (CPT-11).

METHODS

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.

RESULTS

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/ED(50)) 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.

CONCLUSION

It is therefore expected that TP300 will provide an additional treatment option for patients who will undergo chemotherapy with camptothecins.

摘要

目的

鉴定一种新型拓扑异构酶 I 抑制剂，其疗效优于盐酸伊立替康（CPT-11），个体差异较小。

方法

筛选出一种对乳腺癌耐药蛋白（BCRP）阳性细胞有效的新型喜树碱类似物，并生成水溶性前药。以单药和联合其他抗癌药物的方式，在 BCRP 阳性和阴性异种移植模型中检测前药的抗肿瘤活性。

结果

发现了一种新型喜树碱类似物 CH0793076。由于 CH0793076 具有高亲脂性，因此生成了水溶性前药（TP300）。TP300 在酸性溶液中稳定，但在生理 pH 条件下（如血清中）会迅速转化为 CH0793076。这种高效的前药活化将最大限度地减少患者间药代动力学和毒性特征的差异。与 CPT-11 不同，TP300 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，TP300 对 BCRP 阳性和阴性异种移植均显示出抗肿瘤活性，而 CPT-11 对 BCRP 阳性异种移植的活性较低。此外，TP300 的有效剂量范围（MTD/ED50）比 CPT-11 更宽，并且 TP300 与其他抗癌药物（如卡培他滨、奥沙利铂、顺铂、贝伐单抗和西妥昔单抗）联合使用时具有相加或协同的抗肿瘤作用。