Marked antitumor activity of a new potent acronycine derivative in orthotopic models of human solid tumors

S 23906-1 is a novel acronycine derivative selected on the basis of its pot ency in vitro. We investigated the antitumor activity of S 23906-1 against several murine transplantable tumors (C38 colon carcinoma, P388 leukemia, B 16 melanoma, and Lewis lung carcinoma) and in orthotopic models of human lu ng (NCI-H460 and A549), ovarian (IGROV1 and NIH:OVCAR-3), and colorectal ca ncers (HCT116 and HT-29). Against established C38 colon carcinoma, S 23906- 1 administered twice i.v. from 1.56-6.25 mg/kg markedly inhibited tumor gro wth. Treatment at the optimal dose (6.25 mg/kg) induced tumor regression in all of the mice. Acronycine was 16-fold less potent and only, moderately a ctive at the maximum tolerated dose, 100 mg/kg. Against other murine tumors of the former National Cancer Institute panel, S 23906-1 was either only m oderately active or totally inactive. When evaluated in human orthotopic mo dels, S 23906-1 given p.o. or i.v. demonstrated a marked antitumor activity against human carcinomas. In the two human lung cancer models, S 23906-1 i ncreased the survival of the animals in a dose-dependent manner and induced treated versus control values of 162% (NCI-H460) and 193% (A549). Vinorelb ine was less active, with treated versus control values of 119% and 174%, r espectively. A significant survival benefit was also observed against the t wo i.p. ovarian tumors in which S 23906-1 was as active as paclitaxel, indu cing 80% long-term survivors in the NIH: OVCAR-3 model. Lastly, S 23906-1 i nhibited the growth of primary HT-29 and HCT116 colon tumors grafted onto t he cecum as efficiently as irinotecan and eradicated the formation of lymph node, hepatic, and pulmonary metastases in the aggressive HCT116 model. Th e novel spectrum of activity of S 23906-1 compared with existing anticancer agents warrants further preclinical investigation.