PRECLINICAL ANTITUMOR-ACTIVITY OF BIZELESIN IN MICE

Bizelesin (U-77779, NSC 615298), a synthetic analogue of the cytotoxic antibiotic CC-1065, is a bifunctional alkylating agent that produces DNA interstrand cross-links, Bizelesin was evaluated for antitumor act ivity against a broad spectrum of syngeneic murine tumors and human tu mor xenografts in mice, Systemic drug administration produced >6.7 log (10) cell kill against i.p. implanted P388 and L1210 leukemias and 80% tumor-free survivors against s.c. implanted L1210. Against i.p. impla nted B16 melanoma: i.p. drug administration produced a 158% increase i n life span with 25% tumor-free survivors, whereas i.v. drug administr ation produced only a 67% increase in life span with no tumor-free sur vivors, More than 1.0 log(10) cell kill was observed at low mu g/kg do ses in several human tumor models representing diverse histiotypes (CA KI-1 renal, LX-1 lung, HT-29 colon, LOX IMVI and UACC-62 melanomas, an d MX-1 mammary), Less than 1.0 log(10) cell kill was exhibited in othe r tumor models (Lewis lung, colon 38, pancreatic 02, MCF7 mammary, and SK-MEL-3 melanoma), Bizelesin was optimally active when administered i.v. Although antitumor activity was independent of the schedule of ad ministration, greater total doses were tolerated on the more prolonged schedules in any given experiment, Therapeutic doses of bizelesin did not produce delayed deaths, which had previously been observed for th e parent compound CC-1065, However, recovery of lost weight was not at tained until 16-30 days posttherapy, Bizelesin was as active against m urine leukemia sublines resistant to cisplatin, melphalan, and 1,3-bis -(2-chloroethyl)-1-nitrosourea as against the parental line but was to tally inactive against a doxorubicin-resistant subline, The complete c ross-resistance of the doxorubicin-resistant subline to bizelesin sugg ests that bizelesin may be a substrate for the efflux pump that causes multidrug resistance, Due to its breadth of antitumor activity, poten cy, unique mechanism of action, and lack of cross-resistance with othe r alkylating agents, bizelesin was selected for development in clinica l trials by the National Cancer Institute and the Upjohn Company, Toxi cological studies and pharmaceutical development have been completed, and clinical trials are planned to start in the summer of 1996.