Nifedipine improves blood flow and oxygen supply, but not steady-state oxygenation of tumours in perfusion pressure-controlled isolated limb perfusion

Abstract

Isolated limb perfusion allows the direct application of therapeutic agents to a tumour-bearing extremity. The present study investigated whether the dihydropyridine-type Ca 2+ -channel blocker nifedipine could improve blood flow and oxygenation status of experimental tumours during isolated limb perfusion. Perfusion was performed by cannulation of the femoral artery and vein in rats bearing DS-sarcoma on the hind foot dorsum. Perfusion rate was adjusted to maintain a perfusion pressure of 100 -140 mmHg throughout the experiment. Following equilibration, nifedipine was continuously infused for 30 min (8.3 mg min 71 kg 71 BW). During constant-pressure isolated limb perfusion, nifedipine can significantly increase perfusion rate (+100%) and RBC flux (+60%) through experimental leg tumours. 'Steal phenomena' in favour of the surrounding normal tissue and oedema formation were not observed. Despite the increased oxygen availability (+63%) seen upon application of this calcium channel blocker, nifedipine does not result in a substantial reduction of tumour hypoxia, most probably due to an increase in O 2 uptake with rising O 2 supply to the tumour-bearing hind limb. Nifedipine application during isolated limb perfusion can enhance tumour microcirculation and may therefore promote the delivery (pharmacokinetics) of anti-cancer drugs to the tumour and by this improve the efficacy of pressure-controlled isolated limb perfusion.

Anti-Cancer Agents in Proliferation and Cell Death: The Calcium Connection

“…Calcium modulating drugs can be used for enhancement of anti-cancer drug effect, whether it can mitigate side effects of anti-cancer treatment should be explored. Nifedipine, a dihydropyridine-type Ca 2+ -channel blocker improved the blood circulation and reduced hypoxia and hence achieved a better drug delivery towards tumor in an isolated limb perfusion experiment performed in rat bearing tumors [131]. Similarly, verapamil, a calcium channel blocker, improved the sensitivity of tumor to radiation by modifying the tumor vasculature [132].…”