Antitumor effects and toxicities of carboxymethylpullulan-peptide-doxorubicin conjugates.
In vivo antitumor effects of the conjugates of doxorubicin (DXR) with carboxymethylpullulan (CMPul) through tetrapeptide spacers were compared with those of DXR against tumor-bearing rats. CMPul-DXR conjugates bound through Gly-Gly-Phe-Gly and Gly-Phe-Gly-Gly spacers were found to be more potent than DXR after a single intravenous injection in rats bearing Walker 256 carcinosarcoma. These conjugates were also more effective than DXR in rats bearing Yoshida sarcoma. However, CMPul-DXR conjugate bound through Gly-Gly-Gly-Gly was less effective against Walker 256-bearing rats than DXR. Body weight loss of CMPul-DXR conjugates in rats, on the other hand, was less than that of DXR at a DXR dose of 10 mg/kg. Lethal doses of CMPul-DXR conjugates in CDF1 mice were about 3-times higher than that of DXR. These data suggest that the therapeutic index of CMPul-DXR conjugates bound through appropriate peptide spacers was increased more than that of DXR. However, CMPul-DXR conjugates tested were all less effective than DXR against Walker 256 cells in vitro. Also, 125I-labeled CMPul-DXR conjugate accumulated much less in the cells than 14C-DXR.
Nogusa
H
H
Drug Delivery System Institute, Ltd., Chiba, Japan.
Yano
T
T
Kajiki
M
M
Gonsho
A
A
Hamana
H
H
Okuno
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D002279:Carcinoma 256, Walker / Q000473:pathology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005936:Glucans / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D009368:Neoplasm Transplantation; D051381:Rats; D017208:Rats, Wistar; D012517:Sarcoma, Yoshida / Q000473:pathology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005936:Glucans; D004317:Doxorubicin