Masaru Fukui

Antitumor Activities of a Novel 9-Aminoanthracycline (SM-5887) against Mouse Experimental Tumors and Human Tumor Xenografts

The antitumor effects of SM‐5887, a totally synthetic 9‐aminoanthracycline derivative, were evaluated in six murinc experimental tumor systems (P38S, Ehrlich carcinoma, sarcoma 180, Lewis lung carcinoma, B16 melanoma and colon 38) and nine human tumor‐nude mouse systems (one breast cancer, two lung cancers and six gastric cancers). Characteristically SM‐5887 showed excellent antitumor activities, superior to adriamycin (ADR), against human tumor xenografts, although its activities against murine experimental tumors were almost equal to those of ADR. When the human tumors were implanted sc in female athymic mice (BALB/c, nu/nu) and their volume reached 100‐ 300 mm3, SM‐5887 and ADR were injected iv. All nine human tumors tested showed statistically significant responses to SM‐5887, and 7 of them were strongly suppressed in their growth by SM‐5887 so that minimum T/C values were less than 30% at the maximum tolerated dose (MTD, 25 mg/kg) with a single iv injection. Compared with ADR, SM‐5887 was statistically more effective in five tumors (one breast, one lung and three gastric), equal in two tumors (two gastric), and less potent in two tumors (one lung and one gastric). In addition, the 10‐day‐interval repeated iv treatments with SM‐5887 at the MTD (25 mg/kg) resulted in remarkably potent antitumor effects (including complete regression) against human gastric cancer, 4‐1ST, implanted in nude mice without enhancement of toxic effects, SM‐5887 was also effective against ip‐inoculated P388 by oral administration as well as iv injection.

Toxicological aspects of a novel 9-aminoanthracycline, SM-5887

The toxicological characteristics of SM‐5887 were evaluated in mice after a bolus intravenous injection, and compared with those of adriamycin (ADR). The acute toxic signs observed after SM‐5887 administration were body weight decrease, ataxia, hair loss, and myelosuppression. They were qualitatively comparable to those induced by ADR. The 50% lethal dose values determined by 14‐day observation after drug administration were in the range of 32 to 50 mg/kg for SM‐5887 and 16 to more than 20 mg/kg for ADR in four strains of mice. The maximum tolerated doses (MTD) were estimated to be 25 mg/kg for SM‐5887 and 12.5 mg/kg for ADR (no death or body weight loss of more than 3 g occurred). When 14‐day survivors were further observed until 90 days after drug administration, ADR frequently and dose‐independently showed delayed‐type lethal toxicity at doses of more than 10 mg/kg, whereas SM‐5887 did not. The myelosuppression of SM‐5887 was more severe even at a half of the MTD than that of ADR at the MTD, but its recovery was more rapid than that after ADR, In addition, when the drugs were injected into the subplantar region of mouse hind paws, ADR induced a severe inflammatory reaction, whereas SM‐5887 yielded only a slight one. The data suggest that toxic effects of SM‐5887 are more reversible and more controllable than those of ADR.