MRK-17

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 cytotoxicity (ADCC) in therapy of human MDR cancer with the anti-P-glycoprotein antibody.

A mouse‐human chimeric monoclonal antibody (mAb), MH162, against P‐glycoprotein was previously found to be more effective than an all‐mouse mAb (MRK16) in lysis of multidrug‐resistant (MDR) tumor cells by blood mononuclear cells. The present study was performed to identify the effector cells responsible for the chimeric mAb‐dependent cell‐mediated cytotoxicity (ADCC) against MDR cells. The ADCC reaction was assessed by a 6‐h 51Cr release assay. Highly purified lymphocytes (>99%), monocytes (>99%) and neutrophils (>96%) were obtained from peripheral blood of the same healthy donors. A comparison of these three effector cell populations showed no difference between MH162 and its all‐murine counterpart MRK16 in MDR cell lysis by monocytes or neutrophils. But MH162 was more effective than MRK16 in lymphocyte‐mediated lysis of the MDR cells. The lymphocytes responsible for this ADCC had CD16+ Fc receptors. Pretreatment of monocytes with colony‐stimulating factors (IL‐3, GM‐CSF and M‐CSF) caused significant increase in their MH162‐mediated lysis of MDR cells. Another anti‐P‐glycoprotein chimeric mAb (MH171) was also more effective than its murine counterpart MRK17 in lymphocyte‐mediated lysis of MDR cells. These findings suggest that mouse‐human chimeric mAbs may be useful therapeutically for in vivo destruction of MDR cancer cells by the ADCC reaction.