抗がん剤耐性の分子機構と治療への応用

抄録

Research on multidrug resistance (MDR) has spread widely, with the emphasis on the development of therapeutic approaches. This line of research began in the early 1970s. In 1981 and 1982, calcium channel blockers such as verapamil and calmodulin inhibitors were found to enhance the intracellular levels of vincristine (VCR) and adriamycin (ADM) in resistant tumor cells by inhibiting their outward transport and to circumvent MDR in animal experiments. Since these results were noted for verapamil, various other compounds have been investigated to overcome drug resistance. Among these compounds, two compounds were evaluated in our laboratory. The non-immunosuppressive cyclosporin derivative SDZ PSC833 (PSC) has been shown to reverse MDR completely in vitro and in vivo. The second compound is MS-209, a novel quinoline derivative. MS209 completely reversed the resistance against VCR and ADM in vitro. MS209 enhanced the chemotherapeutic effects of VCR and ADM in P388/VCR-and P388/ADM-bearing mice. MS-209 has now started clinical trials in Japan. In addition to these chemical agents, monoclonal antibodies (moAb) against P-glycoprotein such as MRK16 could be useful tools for selective killing of MDR tumor cells. Furthermore another moAb MRK17 can be used against human MDR cells transfected with macrophage-colony stimulating factor (M-CSF) gene. M-CSF can act as an enhancer of antibody dependent cellular cytotoxity (ADCC) in therapy of human MDR cancer with the anti-P-glycoprotein antibody.