Bovine seminal ribonuclease (
BS-RNase) exerts a potent cytotoxic activity when administered intratumorally (i.t.) to the nude mice bearing human
tumors. The ineffective treatment with intravenous (i.v.) or intraperitoneal (i.p.) administration led us to the synthesis of polymeric conjugates with
BS-RNase to prevent it from degradation in the blood vessel. Hydrophilic poly[N-(2-hydroxypropyl)
methacrylamide] (PHPMA) was used for
BS-RNase modification and a PHPMA-
BS-RNase conjugates were prepared. Classic conjugate (P-BS) with
BS-RNase bound to the
polymer by its
oligopeptide site chains was prepared by aminolytic reaction of the
polymer precursor bearing reactive
ester groups situated in the side chains of
polymer, while star-like conjugate (S-BS) was synthesized by the reaction of PHPMA containing end-chain reactive group with
BS-RNase in aqueous
buffer solution at pH 8. In contrast to the total ineffectiveness of free
BS-RNase administered i.v. at a daily dose 10 mg/kg, application of P-BS and S-BS conjugates at doses 2 mg/kg and 0.5 mg/kg caused significant inhibition of the growth of human
melanoma in nude mice. On the base of these results the effect of i.v. administered S-BS on the metastatic process and the survival of C57Bl/6 inbred mice inoculated with
B16 melanoma cells was investigated. Sixty per cent of mice treated with S-BS (0.5 mg/kg/day) survived 100 days without metastatic foci when the experiment terminated. The average survival time of the treated groups was 75.5 days compared to 32.7 days in the control group.
BS-RNase conjugated to water soluble
polymers appears to be the first
BS RNase preparation which exerts anticancer and antimetastatic activity following its
intravenous administration.