Background:

The IC50 values of NPI-2358 is 9.8 ± 2.4 nmol/l, 18 ± 5 nmol/l, 13 ± 1 nmol/l, 14 ± 2 nmol/l, 18 ± 1 nmol/l and 11 nmol/l for HT-29, DU 145, PC-3, MDA-MB-231, NCl-H292 and Jurkat cell lines, respectively[1].

Plinabulin (NPI-2358) is a vascular disrupting agent which binds to the colchicine-binding site of tubulin. NPI-2358 could destabilize tumor vascular endothelial architectural resulting in selective collapse of established tumor vasculature [1].

In vitro: NPI-2358 exhibited anti-tumor activity against various human tumor cell lines. In proliferating human umbilical vein endothelial cells (HUVECs), administration of NPI-2358 at 10 nmol/l induced tubulin depolymerization within 30 min [1]. In an in-vitro model of tumor vascular collapse, NPI-2358 increased HUVEC monolayer permeability in a dose-dependent manner. Plinabulin had also shown the in-vitro cytotoxic activity with IC50 values of 11 ± 5 nmol/l and 4.3 ± 2.2 nmol/l for MES-SA and HL-60 tumor cell lines, respectively[1].

In vivo: In the foot implanted C3H mammary carcinomas or leg implanted KHT sarcomas mice model, 7.5 mg/kg plinabulin (intraperitoneally injected) significantly reduced the transfer constant (K(trans)) and the initial area under curve (IAUC) within 1 hour after injection, reaching a lowest point at 3 h, but returning to normal within 24 h. A dose-dependent decrease in IAUC and K(trans) was seen at 3 h. 12.5 mg/kg and 1.5 mg/kg NPI-2358 showed significant anti-tumour effects in the C3H tumours and the KHT sarcoma, respectively .

Clinical trials: In patients evaluated at a dose of 30 mg/m2, tumor blood flow (Ktrans) showed a 16% to 82% decrease. The half-life of NPI-2358 was 6.06 ± 3.03 hours, clearance was 30.50 ± 22.88 L/h, and distributive volume was 211 ± 67.9 L.

参考文献:
Nicholson B1, Lloyd GK, Miller BR, Palladino MA, Kiso Y, Hayashi Y, Neuteboom ST.  NPI-2358 is a tubulin-depolymerizing agent: in-vitro evidence for activity as a tumor vascular-disrupting agent.Anticancer Drugs. 2006 Jan; 17(1):25-31.
Bertelsen L B, Shen Y Y, Nielsen T, et al.  Vascular effects of plinabulin (NPI-2358) and the influence on tumour response when given alone or combined with radiation[J]. International journal of radiation biology, 2011, 87(11): 1126-1134.
Millward M, Mainwaring P, Mita A, et al.  Phase 1 study of the novel vascular disrupting agent plinabulin (NPI-2358) and docetaxel[J]. Investigational new drugs, 2012, 30(3): 1065-1073.