Therapeutic activity and tissue distribution of ME2303, a new anthracycline containing fluorine, and its metabolites in mice bearing hepatic metastases of Lewis lung carcinoma.
Doxorubicin (DXR) and ME2303, a new fluorine-containing (C'-2) anthracycline derivative, were studied for their tissue distributions--particularly in the plasma, liver and bone marrow--following administration at the maximum tolerated doses to normal mice and mice bearing hepatic metastases of Lewis lung carcinoma. ME2303 was rapidly metabolized and disappeared rapidly from the plasma, liver and bone marrow. Its metabolites--the product of esterolysis (M1) and its reduced derivative at the C-14 position (M2)--remained for a long period except in bone marrow. On the other hand DXR remained in the analyzed tissues for a long period; an especially large amount of DXR was found in the bone marrow even at 24 h after administration of the drug while, in the case of ME2303, by this time even its metabolites had disappeared. The concentrations of M1 and DXR in the liver at 2 h were about 50- and 300-fold higher than their plasma concentrations. The tissue distributions in the normal mice and hepatic-metastases-bearing mice showed no significant differences. Regarding the antitumor effects of ME2303, M1, M2 and DXR in the hepatic-metastases-bearing mice, ME2303 was the most effective compound, and M1 was also active; DXR showed only a marginal effect, and M2 showed no effect.
Iigo
M
M
National Cancer Center Research Institute, Tokyo, Japan.
Nishikata
K
K
Nakajima
Y
Y
Hoshi
A
A
Kadosawa
H
H
Nakajima
S
S
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D014018:Tissue Distribution
C059081:ME 2303; D004317:Doxorubicin