Synthesis and antitumor activity of poly(ethylene glycol)s linked to 5-fluorouracil via a urethane or urea bond.
In order to provide a macromolecular prodrug of 5-fluorouracil (5FU) with reduced side-effects and exhibiting strong antitumor activity, 5FU was covalently linked to poly(ethylene glycol) (PEG) via a urethane or urea bond. For the purpose of evaluating the release behavior of 5FU, the hydrolysis of the urethane or urea bond in the obtained conjugate of PEG-end capped with 5FU was investigated in vitro at 37 degrees C in aqueous solution media. The survival effect for the conjugate was assessed in vivo against p388 lymphocytic leukemia in female CDF1 mice by intraperitoneal (i.p.) transplantation/i.p. injection. The effects of a hydrophobic hexamethylene spacer group, the end group and the number n of ethylene oxide (EO) units in PEG on the release behavior of 5FU and the survival effect were investigated. The release rate of 5FU from the 5FU-terminated PEG conjugates via urethane or urea bond was very fast. However, it became slow with increasing n of EO units in PEG and was depressed by the introduction of hydrophobic spacer group. The 5FU-terminated PEG conjugates obtained exhibited significant survival effects against p388 leukemia mice i.p./i.p. Especially, the methoxy PEG (n = 113)/urethane/hexamethylene/urea/5FU conjugate showed the strongest survival effect among the synthesized 5FU-capped PEG conjugates via urethane or urea bond compared to free 5FU against p388 leukemia mice. These conjugates obtained did not display an acute toxicity even in high dose ranges.
Ouchi
T
T
Department of Applied Chemistry, Faculty of Engineering, Kansai University, Osaka, Japan.
Hagihara
Y
Y
Takahashi
K
K
Takano
Y
Y
Igarashi
I
I
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000737:chemistry* / Q000493:pharmacokinetics; D007941:Leukemia P388 / Q000188:drug therapy / Q000401:mortality; D051379:Mice; D011092:Polyethylene Glycols / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D014508:Urea / Q000737:chemistry*; D014520:Urethane / Q000737:chemistry*
D000970:Antineoplastic Agents; D014520:Urethane; D011092:Polyethylene Glycols; D014508:Urea; D005472:Fluorouracil