Antitumor activity of novel ailanthone derivatives in vitro and in vivo.

Abstract The antitumor activities of two ailanthone derivatives with 15 beta-acyloxy side chains were investigated. The cytotoxic activity of 11 beta, 20-epoxy-1 beta, 11 alpha, 12 alpha-trihydroxy-15-beta-[E)-3-methyl-2-octenoyl) oxypicras-3,13(21)-diene-2,16-dione (SUN2071) and 11 beta, 20-epoxy-1 beta, 11 alpha, 12 alpha-trihydroxy-15 beta-[E)-2-undecenoyl) oxypicras-3,13(21)-diene-2,16-dione (SUN0237) was close to that of bruceantin and vincristine. SUN2071 was shown to be a potent inhibitor of protein synthesis in L1210 cultured cells. When administered i.p. to i.p. inoculated P388 leukemia mice, daily treatment with SUN2071 and SUN0237 significantly increased the lifespan (increases in lifespan in excess of 100% were achieved). These increases were comparable to those achieved with vincristine. The therapeutic ratio of SUN2071 was also close to that of vincristine. However, the compounds were ineffective when administered as a single injection. Daily i.p. treatment with SUN2071 demonstrated significant tumor growth inhibition in mice inoculated s.c. with colon-38 and moderate activity against i.p. L1210 leukemia and i.p. B16 melanoma. The compounds were ineffective when tested against the Lewis lung carcinoma and colon-26. In a preliminary toxicological study, SUN2071 at a therapeutic dose in daily consecutive i.p. injection produced leucopenia.