更新于：2024-11-09
GTI-2040
更新于：2024-11-09
概要
基本信息
药物类型 反义寡核苷酸 |
别名 LOR 2040、LOR-2040、NSC-722929 |
靶点 |
作用机制 RNR抑制剂(核糖核苷酸还原酶复合体抑制剂) |
在研适应症- |
非在研适应症 |
在研机构- |
最高研发阶段无进展临床2期 |
首次获批日期- |
最高研发阶段(中国)- |
特殊审评- |
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序列信息
Sequence Code 29748013
来源: *****
关联
9
项与 GTI-2040 相关的临床试验A Phase II Simon Two-stage Multicenter Study and Pilot Pharmacodynamic Investigation of GTI 2040 in Combination With High Dose Cytarabine (HiDAC) in Refractory and Relapsed Acute Myeloid Leukemia (AML)
Phase I and Pharmacodynamic Study of GTI-2040 (NSC 722929, IND 67368) in Acute Leukemias
A Phase II Study of GTI-2040 in Combination With Docetaxel and Prednisone in Hormone-Refractory Prostate Cancer
100 项与 GTI-2040 相关的临床结果
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100 项与 GTI-2040 相关的转化医学
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100 项与 GTI-2040 相关的专利（医药）
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30
项与 GTI-2040 相关的文献（医药）2022-10-17ACS applied bio materials
Well-Defined pH-Responsive Self-Assembled Block Copolymers for the Effective Codelivery of Doxorubicin and Antisense Oligonucleotide to Breast Cancer Cells
Article
作者: Shahini, Aref ; Rajabian, Nika ; Wu, Yun ; Yan, Lingyue ; Cheng, Chong ; Andreadis, Stelios T. ; Jafari, Amin ; Mohamed, Mohamed Alaa
The worldwide steady increase in the number of cancer patients motivates the development of innovative drug delivery systems for combination therapy as an effective clinical modality for cancer treatment. Here, we explored a design concept based on poly(ethylene glycol)-b-poly(2-(dimethylamino)ethyl methacrylate)-b-poly(2-hydroxyethyl methacrylate-formylbenzoic acid) [PEG-b-PDMAEMA-b-P(HEMA-FBA)] for the dual delivery of doxorubicin (DOX) and GTI2040 (an antisense oligonucleotide for ribonucleotide reductase inhibition) to MCF-7 breast cancer cells. PEG-b-PDMAEMA-b-PHEMA, the precursor copolymer, was prepared through chain extensions from a PEG-based macroinitiator via two consecutive atom transfer radical polymerization (ATRP) steps. Then, it was modified at the PHEMA block with 4-formylbenzoic acid (FBA) to install reactive aldehyde moieties. A pH-responsive polymer-drug conjugate (PDC) was obtained by conjugating DOX to the polymer structure via acid-labile imine linkages, and subsequently self-assembled in an aqueous solution to form DOX-loaded self-assembled nanoparticles (DOX-SAN) with a positively charged shell. DOX-SAN condensed readily with negatively charged GTI2040 to form GTI2040/DOX-SAN nanocomplexes. Gel-retardation assay confirmed the affinity between GTI2040 and DOX-SAN. The GTI2040/DOX-SAN nanocomplex at N/P ratio of 30 exhibited a volume-average hydrodynamic size of 136.4 nm and a zeta potential of 21.0 mV. The pH-sensitivity of DOX-SAN was confirmed by the DOX release study based on the significant cumulative DOX release at pH 5.5 relative to pH 7.4. Cellular uptake study demonstrated favorable accumulation of GTI2040/DOX-SAN inside MCF-7 cells compared with free GTI2040/DOX. In vitro cytotoxicity study indicated higher therapeutic efficacy of GTI2040/DOX-SAN relative to DOX-SAN alone because of the downregulation of the R2 protein of ribonucleotide reductase. These outcomes suggest that the self-assembled pH-responsive triblock copolymer is a promising platform for combination therapy, which may be more effective in combating cancer than individual therapies.
2018-09-01Cancer chemotherapy and pharmacology4区 · 医学
A phase I pharmacokinetic and pharmacodynamic study of GTI-2040 in combination with gemcitabine in patients with solid tumors
4区 · 医学
Article
作者: Cooper, James ; Zwiebel, Anthony ; Malik, Laeeq
PURPOSE:
GTI-2040 is a novel antisense oligonucleotide inhibitor of the R2 subunit of ribonucleotide reductase. This phase I study assessed safety and maximum tolerated dose (MTD) of GTI-2040 in combination with weekly gemcitabine in patients with advanced solid tumors.
METHODS:
GTI-2040 was given as a 14-day continuous intravenous infusion, while gemcitabine was administered on days 1, 8, and 15. This combination was repeated every 4 weeks and study followed a modified 3 + 3 Fibonacci schema. Incidence, severity of adverse events, pharmacokinetics (PK), and pharmacodynamics (PD) was assessed. Responses were assessed using RECIST criteria version 1.0 with CT scans performed after every other cycle.
RESULTS:
A total of 16 patients received at least one dose of GTI-2040/gemcitabine and were included in the safety analysis. The MTD of this regimen is 100 mg/m2/day of GTI-2040 over 14 days combined with 400 mg/m2/day of gemcitabine administered weekly on days 1, 8, and 15. The dose-limiting toxicities (DLTs) included grade 3 fatigue and thrombocytopenia with hematemesis (both at 100/600 mg/m2/day). The most common adverse events were grade 1/2 fatigue, nausea, vomiting, diarrhea, and anorexia. There was no evidence of alteration in gemcitabine PKs. PD modulation of R2mRNA expression in peripheral blood mononuclear cells was observed. No objective tumor response was observed although stable disease was seen in 25% patients.
CONCLUSIONS:
The combination of GTI-2040 and gemcitabine has an acceptable safety profile in a heavily pre-treated patient population with advanced solid tumors. No clear signal of anti-tumor activity was observed; however, several patients had prolonged stable disease.
2017-08-01Journal of cancer research and clinical oncology3区 · 医学
Clinical pharmacology and clinical trials of ribonucleotide reductase inhibitors: is it a viable cancer therapy?
3区 · 医学
Review
作者: Mannargudi, Mukundan Baskar ; Deb, Subrata
PURPOSE:
Ribonucleotide reductase (RR) enzymes (RR1 and RR2) play an important role in the reduction of ribonucleotides to deoxyribonucleotides which is involved in DNA replication and repair. Augmented RR activity has been ascribed to uncontrolled cell growth and tumorigenic transformation.
METHODS:
This review mainly focuses on several biological and chemical RR inhibitors (e.g., siRNA, GTI-2040, GTI-2501, triapine, gemcitabine, and clofarabine) that have been evaluated in clinical trials with promising anticancer activity from 1960's till 2016. A summary on whether their monotherapy or combination is still effective for further use is discussed.
RESULTS:
Among the RR2 inhibitors evaluated, GTI-2040, siRNA, gallium nitrate and didox were more efficacious as a monotherapy, whereas triapine was found to be more efficacious as combination agent. Hydroxyurea is currently used more in combination therapy, even though it is efficacious as a monotherapy. Gallium nitrate showed mixed results in combination therapy, while the combination activity of didox is yet to be evaluated. RR1 inhibitors that have long been used in chemotherapy such as gemcitabine, cladribine, fludarabine and clofarabine are currently used mostly as a combination therapy, but are equally efficacious as a monotherapy, except tezacitabine which did not progress beyond phase I trials.
CONCLUSIONS:
Based on the results of clinical trials, we conclude that RR inhibitors are viable treatment options, either as a monotherapy or as a combination in cancer chemotherapy. With the recent advances made in cancer biology, further development of RR inhibitors with improved efficacy and reduced toxicity is possible for treatment of variety of cancers.
100 项与 GTI-2040 相关的药物交易
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研发状态
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 复发性急性髓细胞白血病 | 临床2期 | 美国 | 2007-08-01 | |
| 去势抵抗性前列腺癌 | 临床2期 | 加拿大 | 2005-01-01 | |
| 复发性乳腺癌 | 临床2期 | 美国 | 2003-10-01 | |
| 男性乳腺肿瘤 | 临床2期 | 美国 | 2003-10-01 | |
| 转移性乳腺癌 | 临床2期 | 美国 | 2003-10-01 | |
| 非小细胞肺癌IIIA期 | 临床2期 | 加拿大 | 2003-10-01 | |
| 非小细胞肺癌IIIB期 | 临床2期 | 加拿大 | 2003-10-01 | |
| 复发性非小细胞肺癌 | 临床2期 | 加拿大 | 2003-10-01 | |
| 复发性前列腺癌 | 临床2期 | 加拿大 | 2003-10-01 | |
| 转移性肾细胞癌 | 临床2期 | 美国 | 2002-03-01 |
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临床结果
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适应症
分期
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临床2期 | 27 | (Pilot) | 觸顧範醖壓廠壓選齋鹹(窪鹽糧獵構餘遞衊襯顧) = 憲鏇繭壓窪齋鑰衊鑰鹽 廠範鹹憲繭繭膚蓋願廠 (鬱憲餘醖餘遞艱選壓願, 選鬱鹽膚窪鑰顧觸艱襯 ~ 窪齋醖膚蓋夢鏇夢窪鏇) 更多 | - | 2015-07-27 | ||
(Phase II Arm) | 觸顧範醖壓廠壓選齋鹹(窪鹽糧獵構餘遞衊襯顧) = 鑰觸窪憲窪獵齋鏇選憲 廠範鹹憲繭繭膚蓋願廠 (鬱憲餘醖餘遞艱選壓願, 願製鑰鹹憲衊糧構製範 ~ 餘衊艱選遞鬱廠鬱積選) 更多 | ||||||
临床2期 | 22 | 願醖鹹積積壓窪蓋鏇簾(繭餘構膚襯醖淵鹽鹹鑰) = 繭遞構憲艱憲願鏇淵簾 夢艱鹹廠繭鹹餘廠齋網 (壓鏇獵選觸齋餘繭齋醖 ) 更多 | - | 2011-04-01 | |||
临床1期 | - | 夢壓衊鏇築壓觸憲鬱網(製襯壓淵淵餘鹽廠壓選) = 艱醖選積獵蓋網選夢築 範構鬱鑰壓選齋憲壓憲 (衊構廠窪窪鹹淵鑰夢衊 ) 更多 | - | 2006-06-20 | |||
夢壓衊鏇築壓觸憲鬱網(製襯壓淵淵餘鹽廠壓選) = 餘願製遞製簾繭膚繭鑰 範構鬱鑰壓選齋憲壓憲 (衊構廠窪窪鹹淵鑰夢衊 ) 更多 |
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