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Antitumor Activity of 1-ß-D-Arabinofuranosylcytosine Conjugated with Polyglutamic Acid and Its Derivative

Department of Medicinal Chemistry and Biochemistry, Teijin Institute for Biomedical Research, Asahigaoka, Hino, Tokyo 191, Japan

Four types of 1-ß-D-arabinofuranosylcytosine (ara-C) conjugates with poly-L-glutamic acid (PLGA) or poly-N⁵-(2-hydroxyethyl)-L-glutamine (PHEG) were prepared in an attempt to enhance the efficacy of the drug in simple dosage schedules. The conjugates were made by linking ara-C to the carboxyl groups of PLGA directly at N-4 of ara-C (ara-C:PLGA) or indirectly through the 2-aminoethylphosphoryl or 6-aminohexylphosphoryl side chain which had been introduced to C-5' of ara-C, 1-[5'-(2-aminoethylphosphoryl)-ß-D-arabinofuranosyl]cytosine:PLGA [araCMP(C₂):PLGA and 1-[5'-(6-aminohexylphosphoryl)-ß-D-arabinofuranosyl]cytosine:PLGA, respectively, or made by converting the remaining carboxyl groups in the PLGA conjugates to the 2-hydroxyethylamide groups {ara-C:PHEG, ara-CMP(C₂):PHEG, 1-[5'-(6-aminohexylphosphoryl)-ß-D-arabinofuranosyl]cytosine:PHEG}. Studies in vitro showed that the conjugates had decreased cytotoxicity against L1210 cells when compared with that of ara-C. Studies in vivo showed that all of the conjugates, except ara-CMP(C₂):PLGA, had a greater antitumor activity than did ara-C in L1210 tumor-bearing BALB/c x DBA/2 F, (hereafter called CD2F₁) mice (inoculum, 1 x 10⁵ cells i.p. on Day 0) which were treated by a single i.p. injection of either the conjugates or the control ara-C on Day 1. The largest antitumor activity [increased life span (ILS) 170%] was observed with a dosage of 50 mg (equivalent ara-C per kg) of ara-C:PHEG. When CD2F₁ mice which had been inoculated i.p. with 1 x 10⁵ L1210 cells were treated with an i.p. injection of 12.5 or 25 mg (equivalent ara-C per kg) of ara-C:PHEG daily for 5 days starting from Day 1, 2 of 5 mice survived more than 42 days, and the ILS of the remaining mice was 153 and 184%. The injections of 3.2 mg (equivalent ara-C per kg) of ara-C:PHEG showed a moderate antitumor activity with an ILS of 113% which was similar to the ILS (119%) found when unconjugated ara-C (400 mg/kg) was used to treat tumor-bearing mice. In in vitro release experiments, ara-C was released slowly from ara-C:PLGA at pH 7.4, and ara-CMP(C₂):PLGA was chemically stable but cleaved by phosphodiesterase, acid phosphatase, and alkaline phosphatase to give mainly 1-ß-D-arabinofuranosylcytosine 5'-monophosphate.

¹ To whom requests for reprints should be addressed.

Received 12/16/81. Accepted 9/12/83.

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