Increased transendothelial permeability of anti-cancer agent carboplatin with the aid of hyperbaric oxygenation

Abstract

1. The objective was to investigate the transport of an anticancer agent carboplatin across the blood–brain barrier in combination with hyperbaric oxygenation treatment. An in vitro well-validated model of bovine brain capillary endothelial cells was used.

2. A transendothelial transport of doxorubicin, a known P-glycoprotein substrate, was enhanced 1.5-fold by verapamil for 2-h incubation at 37°C. A transendothelial permeability coefficient of carboplatin (1.29 × 10⁻³ cm min⁻¹) was also increased 1.8-fold by verapamil.

3. Under the hyperbaric oxygenation conditions (at 0.2 MPa for the first 10 min), the transendothelial transport for 2 h of doxorubicin and carboplatin were increased 1.3- to 1.8-fold by hyperbaric oxygenation, like the suppressive effects of verapamil on P-gp function, without increase of the transport of lucifer yellow, a non P-glycoprotein substrate.

4. Combination of hyperbaric oxygenation treatment and verapamil could not further increase the permeability coefficients of these drugs that were already enhanced by either treatment, implying the P-glycoprotein-mediated carboplatin efflux transport similarly as doxorubicin.

5. Together with our reported high efficacy of carboplatin combined with hyperbaric oxygenation therapy on brain tumours, the present results suggest that carboplatin could be transported by P-glycoprotein, but that this efflux mechanism would be reduced by the hyperbaric oxygenation with the consequences of clinical efficacy.

Keywords::

• Anti-cancer drug
• brain
• carboplatin
• hyperbaric oxygenation
• transport

Acknowledgements

The authors thank Yannick Delplace of CELLIAL Technologies (Lens, France), Dr Hikaru Yabuuchi of GenoMembrane (Yokohama, Japan) and Dr Yu Suzuki, Daisuke Negishi, and Haruka Yamaguchi of their laboratory for their help. This study was supported in part by the Ministry of Education, Science, Sports and Culture of Japan, the Ministry of Health, Labor and Welfare of Japan.