Tumor selective effect of RS-1541 (palmitoyl-rhizoxin) in M5076 sarcoma and host tissues in vivo.
RS-1541 is a 13-O-palmitoyl derivative of rhizoxin, an inhibitor of tubulin polymerization. After intravenous administration of RS-1541 to mice bearing M5076 sarcoma, the maximal inhibitory effect of RS-1541 on DNA synthesis in the tumor was observed 24 h after administration, in agreement with the Cmax of rhizoxin produced from RS-1541, but not with the Cmax of RS-1541. The inhibitory effect after RS-1541 was much higher than that after rhizoxin itself. In the spleen, thymus and bone marrow, DNA synthesis was strongly inhibited by rhizoxin but not by RS-1541. After administration of RS-1541, no significant amounts of rhizoxin were detected in the tissues, except for the tumor. In acute toxicity tests, RS-1541 appeared to be less toxic than rhizoxin. These results indicate that RS-1541 possesses a high tumor-selective effect compared with rhizoxin, because of the selective production of rhizoxin in the tumor after administration of RS-1541.
Tokui
T
T
Analytical and Metabolic Research Laboratories, Sankyo Company, Ltd., Japan.
Maeda
N
N
Kuroiwa
C
C
Sasagawa
K
K
Inoue
T
T
Kawai
K
K
Ikeda
T
T
Komai
T
T
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000633:toxicity; D004273:DNA, Neoplasm / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007275:Injections, Intravenous; D007783:Lactones / Q000494:pharmacology / Q000633:toxicity; D018942:Macrolides; D008297:Male; D051379:Mice; D012513:Sarcoma, Experimental / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism*; D013997:Time Factors
D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D007783:Lactones; D018942:Macrolides; C087843:palmitoyl rhizoxin; C041443:rhizoxin; D013936:Thymidine