Background
Exatecan (DX-8951) is a nonprodrug camptothecin (CPT) derivative, exhibits significant topoisomerase I inhibition [1]. Exatecan (DX-8951) inhibited topoisomerase I with IC50 of 2.2 μM (0.975 μg/ml) [2].
Exatecan (DX-8951) and SN-38 inhibited topoisomerase activity with IC50 values of 0.82 and 2.3 μg/mL, respectively, topoisomerase I was obtained from SUIT-2 cells [3]. Exatecan (DX-8951)(20 ng/ml) induced DNA fragmentation. In an extract from treated SUIT-2 cells, about 60% of DNA was fragmented at the Exatecan (DX-8951) concentration of 20 ng/ml. Exatecan (DX-8951)(0.05 μg/ml, 24 h ) induced the specific features of apoptosis, namely chromatin condensation, nuclear fragmentation and cytoplasmic vacuolation were apparent in SUIT-2 cells [3].
Exatecan (DX-8951) has shown activity in vivo against a wide range of human tumor xenografts in nude mice, including gastric, pancreatic, colon, breast, ovary, and lung tumors [4]. Exatecan (DX-8951) suppressed the growth of human gastric adenocarcinoma SC-6 xenografted into nude mice. When mice were treated i.v. with Exatecan (DX-8951) three times at 4-day intervals, significant inhibition of tumor growth was observed over a wide dose range (3.325 mg/kg to 50 mg/kg of total dose) without toxic death. Its antitumor activity was dependent on the total dose, and at the highest dose of 50 mg/kg, the tumor growth inhibition rate was 92% [2].
参考文献:
[1]. Kumazawa E, Jimbo T, Ochi Y, et al. Potent and broad antitumor effects of DX-8951f, a water-soluble camptothecin derivative, against various human tumors xenografted in nude mice[J]. Cancer chemotherapy and pharmacology, 1998, 42(3): 210-220.
[2]. Mitsui I, Kumazawa E, Hirota Y, Aonuma M, Sugimori M, Ohsuki S, Uoto K, Ejima A, Terasawa H, Sato K. A new water‐soluble camptothecin derivative, DX‐8951f, exhibits potent antitumor activity against human tumors in vitro and in vivo. Japanese journal of cancer research. 1995 Aug;86(8):776-82.
[3]. Takiguchi S, Kumazawa E, Shimazoe T, Tohgo A, Kono A. Antitumor effect of DX‐8951, a novel camptothecin analog, on human pancreatic tumor cells and their CPT‐11‐resistant variants cultured in vitro and xenografted into nude mice. Japanese journal of cancer research. 1997 Aug;88(8):760-9.
[4]. De Jager R, Cheverton P, Tamanoi K, et al. DX‐8951f: summary of Phase I clinical trials[J]. Annals of the New York Academy of Sciences, 2000, 922(1): 260-273.
Exatecan (DX-8951) 是一种非前药喜树碱 (CPT) 衍生物，具有显着的拓扑异构酶 I 抑制作用[1]。 Exatecan (DX-8951) 抑制拓扑异构酶 I，IC50 为 2.2 μM (0.975 μg/ml) [2]。
Exatecan (DX-8951) 和 SN-38 抑制拓扑异构酶活性，IC50 值分别为 0.82 和 2.3 μg/mL，拓扑异构酶 I 是从 SUIT-2 细胞中获得的[3]。 Exatecan (DX-8951)(20 ng/ml) 诱导 DNA 断裂。在来自处理过的 SUIT-2 细胞的提取物中，约 60% 的 DNA 在 Exatecan (DX-8951) 浓度为 20 ng/ml 时发生片段化。 Exatecan (DX-8951)(0.05 μg/ml, 24 h )诱导细胞凋亡的特异性特征，即在SUIT-2细胞中染色质浓缩、核碎裂和细胞质空泡化明显[3].< /p>\n
Exatecan (DX-8951) 已在体内显示出对裸鼠体内多种人类肿瘤异种移植物的活性，包括胃癌、胰腺癌、结肠癌、乳腺癌、卵巢癌和肺癌[4] . Exatecan (DX-8951) 抑制异种移植到裸鼠体内的人胃腺癌 SC-6 的生长。当小鼠接受静脉注射治疗时Exatecan (DX-8951) 以 4 天为间隔 3 次，在宽剂量范围（3.325 mg/kg 至 50 mg/kg 总剂量）内观察到肿瘤生长显着抑制，且无毒性死亡。其抗肿瘤活性与总剂量有关，在最高剂量50 mg/kg时，肿瘤生长抑制率为92%[2]。
Protocol
| Cell experiment [1]: |
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Cell lines
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32 malignant cell lines
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Preparation Method
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Thus 500-20,000 cells/well in 150 u1 of medium were plated in 96-well flat-bottomed microplates and grown for 24h (P388, CCRF-CEM and K562 cells for 4h), the Exatecan (DX-8951) (in 50 μl medium/well), or the medium alone as a control was added, and the cells were cultured for an additional 3 days. Then calculated Growth inhibition of 50% (GI50) .
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Reaction Conditions
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Different concentrations for 24 h
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Applications
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Exatecan (DX-8951) showed strong antiproliferating activity,and the mean GI50 values against breast cancers colon cancers, stomach cancers, and lung cancers were 2.02 ng/ml, 2.92 ng/ml, 1.53 ng/ml, and 0.877 ng/ml respectively.
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| Animal experiment [2]: |
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Animal models
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Male 6-week-old BALB/c-nu/nu nude mice
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Preparation Method
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The human tumor lines inoculated s.c. into nude mice and maintained as solid tumors. Various human tumors maintained in nude mice were excised and
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Dosage form
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50 mg/kg, i.v.
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Applications
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The q4d×4 schedule more readily caused the regressive effects of Exatecan (DX-8951) compared with the q7d×3, and a schedule of q4d×3 more frequently permitted regrowth of tumors than did the q4d×4 schedule.
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参考文献:
[1]: Mitsui I, Kumazawa E, Hirota Y, Aonuma M, Sugimori M, Ohsuki S, Uoto K, Ejima A, Terasawa H, Sato K. A new water坼soluble camptothecin derivative, DX坿951f, exhibits potent antitumor activity against human tumors in vitro and in vivo. Japanese journal of cancer research. 1995 Aug;86(8):776-82.
[2]:Kumazawa E, Jimbo T, Ochi Y, et al. Potent and broad antitumor effects of DX-8951f, a water-soluble camptothecin derivative, against various human tumors xenografted in nude mice[J]. Cancer chemotherapy and pharmacology, 1998, 42(3): 210-220.
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