Antiproliferative activity, mechanism of action and oral antitumor activity of CP-4126, a fatty acid derivative of gemcitabine, in in vitro and in vivo tumor models.
Antiproliferative activity, mechanism of action and oral antitumor activity of CP-4126, a fatty acid derivative of gemcitabine, in in vitro and in vivo tumor models.
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DOI：
10.1007/s10637-009-9377-7
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发表时间：
2011-06
影响因子：
3.4
通讯作者：
Peters, Godefridus J.
中科院分区：
文献类型：
--
作者：
Bergman, Andries M.;Adema, Auke D.;Balzarini, Jan;Bruheim, Skjalg;Fichtner, Iduna;Noordhuis, Paul;Fodstad, Oystein;Myhren, Finn;Sandvold, Marit L.;Hendriks, Hans R.;Peters, Godefridus J.
关键词：
吉西他滨是一种脱氧胞苷（dCyd）类似物，在白血病和实体瘤中具有活性，需要通过脱氧胞苷激酶（dCK）进行磷酸化。膜转运减少是吉西他滨耐药的一种机制。为了促进吉西他滨的摄取并延长其在细胞中的滞留，合成了一种亲脂性前药（CP-4126），其中在5′位酯化了一个反式脂肪酸。在对阿糖胞苷、另一种dCyd类似物或吉西他滨耐药的细胞系中测试CP-4126。吉西他滨和衍生物的活性在亲本细胞系中相当，而在dCK缺陷细胞中，所有化合物均无活性。然而，核苷转运的抑制使吉西他滨的IC 50增加了200倍，但对CP-4126没有增加，这强调了核苷转运蛋白的独立性。对于体内评价，每三天腹膜内处理携带人异种移植物的裸鼠，以最大耐受剂量给药五次。在黑色素瘤、肉瘤、肺癌、前列腺癌、胰腺癌和乳腺癌异种移植物中，吉西他滨和CP-4126具有同等和高度的有效性;在其他四种异种移植物中，吉西他滨和CP-4126具有中等但同等的活性。与吉西他滨相反，CP-4126可以口服给药，具有时间表和剂量依赖性毒性和抗肿瘤活性。在结肠癌异种移植物中，口服给药CP-4126的抗肿瘤活性与腹腔内给药药物相等。总之，CP-4126不依赖于膜转运蛋白。在几种异种移植物中，腹膜内给予CP-4126与吉西他滨一样有效，并且CP-4126在口服给药时耐受。CP-4126似乎是一种很有前途的抗癌新药。
Gemcitabine is a deoxycytidine (dCyd) analog with activity in leukemia and solid tumors, which requires phosphorylation by deoxycytidine kinase (dCK). Decreased membrane transport is a mechanism of resistance to gemcitabine. In order to facilitate gemcitabine uptake and prolong retention in the cell, a lipophilic pro-drug was synthesized (CP-4126), with an elaidic fatty acid esterified at the 5′position. CP-4126 was tested in cell lines resistant to cytarabine, another dCyd analog or gemcitabine. Activity of gemcitabine and the derivative was comparable in the parent cell lines, while in dCK deficient cells all compounds were inactive. However, inhibition of nucleoside transport increased the IC50 for gemcitabine up to 200-fold, but not for CP-4126, underlining the independence of a nucleoside transporter. For in vivo evaluation, nude mice bearing a human xenograft were treated intraperitoneally every third day for five doses at the maximal tolerated dose. In melanoma, sarcoma, lung, prostate, pancreatic and breast cancer xenografts, gemcitabine and CP-4126 were equally and highly effective; in four other xenografts moderately but equally active. In contrast to gemcitabine, CP-4126 could be administered orally, with a schedule and dose dependent toxicity and antitumor activity. In a colon cancer xenograft, antitumor activity of orally administered CP-4126 was equal to the intraperitoneally administered drug. In conclusion, CP-4126 is membrane transporter independent. Intraperitoneally administered CP-4126 was as effective as gemcitabine in several xenografts and CP-4126 is tolerated when orally administered. CP-4126 seems to be a promising new anticancer drug.
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DOI：
10.1093/jnci/83.11.757
发表时间：
1991-06-05
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
MONKS, A;SCUDIERO, D;BOYD, M
通讯作者：
BOYD, M
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
5.8
作者：
Ramalingam, Suresh;Belani, Chandra
通讯作者：
Belani, Chandra
影响因子：
6.2
作者：
Abbruzzese, JL
通讯作者：
Abbruzzese, JL
影响因子：
6.4
作者：
PETERS, GJ;WETS, M;PINEDO, HM
通讯作者：
PINEDO, HM