Anticancer activity of the structurally novel antibiotic Cl-920 and its analogues

Abstract

Cl-920 is a structurally novel phosphate ester antibiotic that contains an unsaturated lactone and a conjugated triene system. It has potent antileukemic activity in mice. At doses of 25 mg/kg given i.p. once daily for 5 days to mice bearing approximately 10(7) L1210 leukemia cells, Cl-920 is curative in about 10% of the mice. Life span increases in noncured mice are typically in excess of 150%. The unsaturated lactone and phosphate ester moieties are required for activity against L1210 leukemia. Ring hydroxylation or removal of the terminal hydroxyl group have only modest effects on activity. Schedule studies suggest that prolonged exposure to low levels of Cl-920 is considerably more toxic than is daily or intermittent administration. Daily administration produces optimal activity against L1210 leukemia. Administration i.p. and i.v. of Cl-920 produce roughly equal toxicity and equal activity against an i.p. implant of L1210 leukemia. Cl-920 is inactive when given p.o. or s.c. Cl-920 failed to show confirmed activity against the following tumors in mice: M5076 sarcoma, B16 melanoma, and Ridgway osteogenic sarcoma. The lack of solid tumor activity in mice may be caused by a transport deficiency similar to that found with methotrexate.