BACPTDP: a water-soluble camptothecin pro-drug with enhanced activity in hypoxic/acidic tumors.
BACPTDP: a water-soluble camptothecin pro-drug with enhanced activity in hypoxic/acidic tumors.
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DOI：
10.1007/s00280-010-1388-8
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发表时间：
2011-04
影响因子：
3
通讯作者：
Morgan, Lee Roy
中科院分区：
文献类型：
--
作者：
Adams, David J.;Waud, William R.;Wani, Mansukh C.;Manikumar, Govindarajan;Flowers, James L.;Driscoll, Timothy A.;Morgan, Lee Roy
关键词：
缺氧是实体瘤的常见特征。缺氧诱导因子-1（HIF-1）的上调发生在大多数原发性恶性肿瘤和三分之二的转移瘤中，而大多数正常组织是阴性的。HIF-1诱导糖酵解表型，其产生酸性细胞外微环境和相关的pH梯度，使得弱酸性药物被选择性地摄取并保留在酸性肿瘤中。7-丁基-10-氨基-喜树碱（BACPT）是可以利用肿瘤pH梯度以增强选择性的药剂的主要实例。本文研究了BACPT的体外抗肿瘤活性及其水溶性二肽酯BACPTDP的体内抗肿瘤活性。通过癌细胞系和人神经母细胞瘤（IMR-32）、结肠癌（HT 29）、卵巢癌（SK-0 V-3）、胰腺癌（Panc-1）、神经胶质瘤（SF-295）和非小细胞肺癌（NCI-H460）的鼠异种移植模型中的增殖试验评价抗肿瘤活性。在人神经母细胞瘤和胰腺肿瘤细胞系的单层培养物中以及在结肠癌和原发性卵巢癌的三维组织培养物中，与已建立的药物相比，BACPT具有上级抗增殖活性。在IMR-32、HT 29、SF-295和NCI-H460异种移植物中，BACPTDP的抗肿瘤活性与伊立替康相当，在SK-0 V-3和Panc-1中显著更高，其中观察到完全消退。BACPT与吉西他滨的组合在Panc-1细胞中产生相加协同相互作用，其独立于药物比例，并且当吉西他滨在BACPT之前24小时施用时是最佳的。BACPTDP是一种水溶性喜树碱前药，可自发产生脂溶性活性剂BACPT。这种拓扑异构酶抑制剂利用实体瘤生理学来改善对多种肿瘤类型的选择性和活性，特别有希望用于治疗小儿神经母细胞瘤和胰腺癌。
Hypoxia is a common feature of solid tumors. Up-regulation of hypoxia-inducing factor-1 (HIF-1) occurs in the majority of primary malignant tumors and in two-thirds of metastases, while most normal tissues are negative. HIF-1 induces the glycolytic phenotype, which creates an acidic extracellular microenvironment and associated pH gradient such that drugs that are weak acids are selectively taken up and retained in acidic tumors. 7-Butyl-10-amino-camptothecin (BACPT) is a prime example of an agent that can exploit the tumor pH gradient for enhanced selectivity. This study profiles the antitumor activity of BACPT in vitro and its water-soluble dipeptide ester, BACPTDP, in vivo. Antitumor activity was evaluated by proliferation assays in cancer cell lines and in murine xenograft models for human neuroblastoma (IMR-32), colon (HT29), ovarian (SK-OV-3), pancreatic (Panc-1), glioma (SF-295) and non-small-cell lung (NCI-H460) cancers. BACPT had superior antiproliferative activity compared to established drugs in monolayer cultures of human neuroblastoma and pancreatic tumor cell lines and in 3-dimensional histocultures of colon and primary ovarian cancer. Antitumor activity of BACPTDP was comparable to irinotecan in IMR-32, HT29, SF-295 and NCI-H460 xenografts, significantly greater in SK-OV-3 and in Panc-1 where complete regressions were observed. Combination of BACPT with gemcitabine produced additive to synergistic interactions in Panc-1 cells that were independent of drug ratio and optimal when gemcitabine was administered 24 h prior to BACPT. BACPTDP is a water-soluble camptothecin pro-drug that spontaneously generates the lipid-soluble active agent, BACPT. This topoisomerase inhibitor exploits solid tumor physiology for improved selectivity and activity against multiple tumor types with particular promise for use in treating pediatric neuroblastoma and pancreatic carcinoma.
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