Vascular effects of plinabulin (NPI-2358) and the influence on tumour response when given alone or combined with radiation

• Published in: International journal of radiation biology Vol. 87; no. 11; pp. 1126 - 1134
• Main Authors: Bertelsen, Lotte B., Shen, Yuan Yuan, Nielsen, Thomas, Stødkilde-Jørgensen, Hans, Kenneth Lloyd, G., Siemann, Dietmar W., Horsman, Michael R.
• Format: Journal Article
• Language: English
• Published: England Informa Healthcare 01.11.2011; Taylor & Francis
• Subjects: Animals; Antineoplastic Agents - therapeutic use; C3H mammary carcinoma; Chemoradiotherapy; Diketopiperazines; Dose-Response Relationship, Drug; Female; Imidazoles - therapeutic use; KHT sarcoma; magnetic resonance imaging; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - pathology; Mammary Neoplasms, Experimental - radiotherapy; Mice; Mice, Inbred C3H; Piperazines - therapeutic use; Plinabulin (NPI-2358); radiation; Sarcoma, Experimental - drug therapy; Sarcoma, Experimental - pathology; Sarcoma, Experimental - radiotherapy; vascular targeting
• ISSN: 0955-3002; 1362-3095
• DOI: 10.3109/09553002.2011.605418

Abstract Purpose: This study investigated the anti-tumour effects of the novel vascular disrupting agent plinabulin (NPI-2358) when given alone or combined with radiation. Materials and methods: Foot implanted C3H mammary carcinomas or leg implanted KHT sarcomas were used, with plinabulin injected intraperitoneally. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measurements were made with gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) on a 7-tesla magnet. Treatment response was assessed using regrowth delay (C3H tumours), clonogenic survival (KHT sarcomas) or histological estimates of necrosis for both models. Results: Plinabulin (7.5 mg/kg) significantly reduced the initial area under curve (IAUC) and the transfer constant (Ktrans) within 1 hour after injection, reaching a nadir at 3 h, but returning to normal within 24 h. A dose-dependent decrease in IAUC and Ktrans, was seen at 3 h. No significant anti-tumour effects were observed in the C3H tumours until doses of 12.5 mg/kg were achieved, but started at 1.5 mg/kg in the KHT sarcoma. Irradiating tumours 1 h after injecting plinabulin enhanced response in both models. Conclusions: Plinabulin induced a time- and dose-dependent decrease in tumour perfusion. The KHT sarcoma was more sensitive than the C3H tumour to the anti-tumour effects of plinabulin, while radiation response was enhanced in both models.