No abstract

Since poly(α‐malic acid) is a biodegradable and bioabsorbable lactic acid type polyester having pendent carboxylic acid groups, it is of interest for application as the polymer carrier to covalently attach both a parent drug and a targeting agent. In order to provide a macromolecular prodrug of 5‐fluorouracil (5FU) with reduced side‐effects and exhibiting high antitumor activity, the covalent attachment of 5FU to poly(α‐malic acid) through hydrophobic spacer groups, ester or amide and carbamoyl groups was carried out. In order to estimate the release behavior of 5FU from poly(α‐malic acid)‐5FU conjugates, the hydrolysis of the pendent ester or amide and carbamoyl groups in the conjugates obtained was investigated in vitro using various kinds of aqueous solution at 37°C. The effect on prolongation of life was tested in vivo against p‐388 lymphocytic leukemia in female CDF1 mice by intraperitoneal (i.p.) i.p. injection. These poly(α‐malic acid) 5FU conjugates gave a high survival rate and did not display acute toxicity in the high dose range of 200–800 mg/kg.

To provide a macromolecular prodrug of 5-fluorouracil (5FU) with reduced side-effects, an affinity for tumor cells and exhibiting the high antitu mor activity, the covalent attachment of 5FU to chitosan and chitin through hexamethylene spacers via carbamoyl bonds was carried out. In vivo testing against p-388 lyphocytic leukemia in female CDF1 mice by intraperitoneal in jection ( i.p.) and the in vivo growth-inhibitory effect on Meth-A fibrosarcoma in SPF-C3H/He mice by subcutaneous injection (s.c.)/intravenous injection (i.v.) were evaluated. The effects of the degree of polymerization of chitosan and the degree of 5FU substitution per glucosamine unit on the prolongation of life were investigated. The chitosan-5FU and chitin-5FU conjugates exhibited high survival effects and chitosan-5FU conjugate showed significant growth- inhibitory effect on Meth-A fibrosarcoma. These chitosan-5FU and chitin-5FU conjugates did not display any acute toxicity in the 800 mg/kg dose range.

No abstract

In order to provide a polymeric drug of 5-fluorouracil (5FU) with reduced side-effects, having affinity for tumor cells and exhibiting high antitumor activity, four kinds of chitosan derivatives were synthesized carrying 5FUs through some kinds of spacers via ether, amide, ester, or carbamoyl bonds. The release behaviors of 5FU and 5FU residues were studied in vitro at 37 "C in various aqueous media. The antitumor activity was tested against p-388 lymphocytic leukemia in female CDF, mice in vivo by intraperitoneal injection of the polymeric drugs followed by intraperitoneal injection of the leukemia cells (i. p./i.p.). Chitosan fixing 5FU at 2-position through a hexamethylene spacer and carbamoyl linkages (9) exhibits a higher effect with respect to prolongation of life than free 5FU. The chitosan-5FU conjugates obtained do not display acute toxicity in the high dose range.