Exatecan (DX-8951)

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].

References:
[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]。