Contribution of serum lipoproteins as carriers of antitumour agent RS-1541 (palmitoyl rhizoxin) in mice.

The tumour uptake as well as the anti-tumour activity of RS-1541 (palmitoyl rhizoxin), a potent antineoplastic agent, were investigated in mice bearing M5076 sarcoma. After intravenous administration, 14C-RS-1541 preferentially bound to the lipoproteins, to which 14C-rhizoxin did not bind. 14C-RS-1541 showed persisting high concentrations of radioactivity in the plasma (T 1/2 alpha, 4.9 h). The uptake of radioactivity by the tumour was second to those by the liver and spleen, and several times greater than those by the other tissues. Selective and sustained uptake by the tumour was also demonstrated by whole-body autoradiography. A considerable amount of rhizoxin was detected only in the tumour after administration of 14C-RS-1541, and the area under the tissue-concentration-time curve (AUCt) and the mean residence time (MRT) of rhizoxin in the tumour were much higher than those after administration of 14C-rhizoxin itself. The rhizoxin formation in the tumour was significantly reduced by chloroquine, a lysosomal enzyme inhibitor. RS-1541 showed a higher therapeutic activity than rhizoxin. At a 4 mg kg-1 dose, the maximum growth inhibition was 92% for RS-1541 and 41% for rhizoxin. These results indicate that RS-1541, but not rhizoxin, is taken up by the tumour via endocytosis, most likely via the low-density-lipoprotein receptor, after binding to lipoproteins. Thus, RS-1541 was considered to exhibit sustained high concentration in tumours and potent anti-tumour activity.