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

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 (K^trans) 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 K^trans, 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.

Keywords::

• Plinabulin (NPI-2358)
• vascular targeting
• radiation
• C3H mammary carcinoma
• KHT sarcoma
• magnetic resonance imaging

Acknowledgements

The authors would like to thank Ms Dorthe Grand, Ms Pia Schjerbeck, Ms Inger Marie Horsman, Mr Mogens Johannsen and Ms Chris Campo for their excellent technical assistance. This work was supported by funding from Nereus Pharmaceuticals, and grants from the Danish Cancer Society, and the National Cancer Institute (Public Health Service Grant CA084408).

Declaration of interest

G. Kenneth Lloyd is Chief Scientific Officer and Senior Vice President of Research and Development for Nereus Pharmaceuticals Inc. The other authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.