DEVELOPMENT OF NEW SEMISYNTHETIC TAXANES

新型半合成紫杉烷的开发

基本信息

批准号：
6376376
负责人：
RALPH James BERNACKI
金额：
$ 31.97万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-07-01 至 2003-06-30
项目状态：
已结题

项目摘要

Taxanes are highly promising agents for the treatment of human cancers. However, the efficacy of taxane therapy using either paclitaxel or docetaxel may be limited due to resistance to these drugs. Clinical resistance to both paclitaxel and docetaxel is often associated with the amplification of P-glycoprotein (Pgp); MRP and LRP appear to be less of a factor in taxane resistance. Several Pgp positive tumor cells demonstrate cross-resistance to paclitaxel by decreasing their intracellular drug levels. Clearly, second generation taxanes that have improved therapeutic activity against multi-drug resistant (MDR1 gene mediated) tumors would be advantageous. To circumvent Pgp-associated multi-drug resistance to paclitaxel, we are proposing two major strategies. First, the development of cytotoxic analogs of paclitaxel that are not substrates for Pgp. Second, the development of non- cytotoxic taxane-based reversal agents (tRAs) which modulated Pgp- mediated efflux of active agents. In the first strategy, we will evaluate new taxanes synthesized by Dr. Ojimi, SUNY Stony Brook, with potentially higher cytotoxic activity against Pgp-resistant human cancer cell lines as compared with either paclitaxel or docetaxel. To this end, we have evaluated several hundred taxanes and have selected lead compounds (i.e., IDN5109, IDN5111, and fluoro-taxanes 97003/4) for further pre-clinical drug development. These agents have demonstrated up to 30-fold higher anti-tumor activity than either paclitaxel or docetaxel against mdr1 Pgp containing human tumor cell lines (e.g., MDA435/LCC6/MDR1 breast ca., UO31 renal ca. and HCT15 colon ca.). Recent results, from our laboratory and others, have indicated that IDN5109 AND idn511, in comparison to paclitaxel, display equivalent efficacy against drug-sensitive, human tumor xenografts in mice and significantly improved activity against multi-drug resistant tumors. In the second strategy, we are evaluating tRAs and developing their combinations with paclitaxel, new-taxanes and/or doxorubicin for the treatment of Pgp- resistant tumors. We have recently discovered several tRAs (e.g., 96023) which in combination with paclitaxel or IDN5109, resulted in an additional 20 to 30-fold increase synergy) against multi-drug resistant (Pgp positive) tumor cell lines. We will now devote significant effort to defining and optimizing the preclinical anti-tumor spectrum for these new agents and significant effort to defining and optimizing the pre- clinical anti-tumor spectrum for these new agents and treatment. New in vivo studies have demonstrated significant therapeutic efficacy in nude athymic mice for a combination of IDN5109 with 96023 against the MDA435/LCC6/MDR1 breast tumor xenograft, a highly drug resistant tumor. Pharmacokinetic approaches will be used to investigate the cellular uptake and retention of new taxanes, as well as the modulation of Pgp- mediated efflux of drugs by tRA, both in vivo and in vitro. Using tRNA 96023 as a selecting agent, clothes containing mutated mdr sequences have recently been generated which will be used in the mapping of the taxane-binding site within Pgp. This and other data accumulated with these new semi-synthetic taxanes will be used to generate three- dimensional structural activity relationships (Q-SAR), elucidating the molecular interactions of these taxanes and aiding our design of more selective compounds. It is anticipated that this research will lead to the discovery and development of new taxanes and reversal agents with significant anti-tumor activity against multi-drug-resistant tumors have mdr1 Pgp expression.

紫杉烷类药物是治疗人类癌症的极有前景的药物。然而，由于对这些药物的耐药性，使用紫杉醇或多西紫杉醇的紫杉烷疗法的疗效可能会受到限制。对紫杉醇和多西紫杉醇的临床耐药性通常与 P-糖蛋白 (Pgp) 的扩增有关； MRP 和 LRP 似乎不是紫杉烷耐药性的一个因素。一些 Pgp 阳性肿瘤细胞通过降低其细胞内药物水平表现出对紫杉醇的交叉耐药性。显然，对多重耐药（MDR1 基因介导的）肿瘤具有改善的治疗活性的第二代紫杉烷将是有利的。为了规避 Pgp 相关的紫杉醇多药耐药性，我们提出了两种主要策略。首先，开发不是 Pgp 底物的紫杉醇细胞毒性类似物。其次，开发基于非细胞毒性紫杉烷的逆转剂(tRA)，其调节Pgp介导的活性剂的流出。在第一个策略中，我们将评估由纽约州立大学石溪分校的 Ojimi 博士合成的新紫杉烷，与紫杉醇或多西紫杉醇相比，该紫杉烷对 Pgp 耐药的人类癌细胞系具有潜在更高的细胞毒活性。为此，我们评估了数百种紫杉烷，并选择了先导化合物（即 IDN5109、IDN5111 和氟紫杉烷 97003/4）用于进一步的临床前药物开发。这些药物对含有 mdr1 Pgp 的人肿瘤细胞系（例如 MDA435/LCC6/MDR1 乳腺癌细胞、UO31 肾细胞和 HCT15 结肠细胞）的抗肿瘤活性比紫杉醇或多西紫杉醇高出 30 倍。我们实验室和其他实验室的最新结果表明，与紫杉醇相比，IDN5109 和 idn511 对小鼠体内药物敏感的人类肿瘤异种移植物显示出相同的功效，并且显着提高了对多重耐药肿瘤的活性。在第二个策略中，我们正在评估 tRA 并开发它们与紫杉醇、新紫杉烷和/或多柔比星的组合，用于治疗 Pgp 耐药肿瘤。我们最近发现了几种 tRA（例如 96023），它们与紫杉醇或 IDN5109 联合使用，对多重耐药（Pgp 阳性）肿瘤细胞系产生额外 20 至 30 倍的协同作用。我们现在将投入大量精力来定义和优化这些新药的临床前抗肿瘤谱，并努力定义和优化这些新药和治疗的临床前抗肿瘤谱。新的体内研究表明，IDN5109 与 96023 组合在无胸腺裸鼠中对 MDA435/LCC6/MDR1 乳腺肿瘤异种移植物（一种高度耐药的肿瘤）具有显着的治疗效果。药代动力学方法将用于研究新紫杉烷类药物的细胞摄取和保留，以及体内和体外 tRA 对 Pgp 介导的药物流出的调节。使用 tRNA 96023 作为选择剂，最近生成了含有突变 mdr 序列的衣服，它将用于绘制 Pgp 内紫杉烷结合位点的图谱。这些新的半合成紫杉烷积累的数据和其他数据将用于生成三维结构活性关系（Q-SAR），阐明这些紫杉烷的分子相互作用，并帮助我们设计更具选择性的化合物。预计这项研究将导致新紫杉烷类和逆转剂的发现和开发，这些紫杉烷类和逆转剂对具有 mdr1 Pgp 表达的多重耐药肿瘤具有显着的抗肿瘤活性。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

High-resolution magnetic resonance imaging of the efficacy of the cytosine analogue 1-[2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl]-N(4)-palmitoyl cytosine (CS-682) in a liver-metastasis athymic nude mouse model.

高分辨率磁共振成像显示胞嘧啶类似物 1-[2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl]-N(4)-palmitoyl cytosine (CS-682) 在肝脏中的功效

DOI：
发表时间：
2003
期刊：
Cancer research
影响因子：
11.2
作者：
Wu,Ming;Mazurchuk,Richard;Chaudhary,NeetaD;Spernyak,Joseph;Veith,Jean;Pera,Paula;Greco,William;Hoffman,RobertM;Kobayashi,Tomowo;Bernacki,RalphJ
通讯作者：
Bernacki,RalphJ

The 4'-O-benzylated doxorubicin analog WP744 overcomes resistance mediated by P-glycoprotein, multidrug resistance protein and breast cancer resistance protein in cell lines and acute myeloid leukemia cells.

4-O-苄基化阿霉素类似物 WP744 克服了细胞系和急性髓系白血病细胞中 P-糖蛋白、多药耐药蛋白和乳腺癌耐药蛋白介导的耐药性。

DOI：
10.1007/s10637-006-9018-3
发表时间：
2007
期刊：
Investigational new drugs
影响因子：
3.4
作者：
Brooks,TracyA;O'Loughlin,KieranL;Minderman,Hans;Bundy,BrianN;Ford,LaurieA;Vredenburg,MichaelR;Bernacki,RalphJ;Priebe,Waldemar;Baer,MariaR
通讯作者：
Baer,MariaR

Partial circumvention of P-glycoprotein-mediated multidrug resistance by doxorubicin-14-O-hemiadipate.

阿霉素-14-O-半己二酸部分规避 P-糖蛋白介导的多药耐药性。