Investigation into the Activity of Zoledronic Acid and Nimesulide in a Model of Bone Cancer Pain

Clare Doris, Gillian Muirhead, Julie McLaughlin, Cath Waters. Aptuit Ltd, Edinburgh, United Kingdom.

Cancer patients commonly have associated metastatic bone cancer pain. This unique chronic pain state is particularly difficult to control. Aside from morphine and other opiate based compounds used in the management of bone cancer pain, both bisphosphonates and COX-2 inhibitors are compounds of particular interest, due to their anti-tumour and analgesic properties. In this study, two compounds (bisphosphonate: Zoledronic acid (ZA) and a COX-2 inhibitor: Nimesulide (NIM)) were investigated for their in-vitro anti-tumour properties and their in-vivo effects in an animal model of bone cancer pain.

Using an in vitro 3 (4,5 dimethylthiazol 2 yl) 2,5 diphenyltetrazolium bromide (MTT) assay, the potential growth-inhibitory activity of the test substances, ZA and NIM on the rat mammary tumour cell line Walker 256 was investigated. Concurrently, a modified model of bone cancer pain was established through the inoculation of Syngenic Walker 256 mammary gland carcinoma cells into the right tibia medullary cavity of female Sprague-Dawley rats. In this model, both ZA (30 ug/kg, s.c.) and NIM (20 mg/kg, p.o.) were administered chronically for every 2/3 days up to Day 20, along with a vehicle control (up to 7 animals per group) from the day of surgery, to investigate the prophylactic effects on the development of the mechanical allodynia using von Frey filaments.

In the MTT assay, the growth-inhibitory activity of ZA and NIM was found to be >10 μM and >150 μM, respectively. In the in-vivo model, from Day 12 post-surgery, the effects of ZA had a significant effect increasing up to Day 20 (P<0.001), where the withdrawal threshold was 10.13 ± 0.97g compared to the vehicle control data of 1.93 ± 0.55g. Similarly, NIM had a significant effect on the development of mechanical allodynia, with significant effects evident from Day 10 up to Day 20 (P<0.001), where the withdrawal threshold was 7.08 ± 0.81g compared to the vehicle control data of 2.81 ± 0.38g.

In conclusion, this data supports the finding that both bisphosphonates and COX-2 inhibitors will play an important role in the future treatment of bone cancer pain.