Preclinical antitumor activity of bizelesin in mice.
Bizelesin (U-77779, NSC 615291), 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 activity against a broad spectrum of syngeneic murine tumors and human tumor xenografts in mice. Systemic drug administration produced >6.7 log10 cell kill against i.p. implanted P388 and L1210 leukemias and 80% tumor-free survivors against s.c. implanted L1210. Against i.p. implanted B16 melanoma, i.p. drug administration produced a 158%; increase in life span with 25% tumor-free survivors, whereas i.v. drug administration produced only a 67% increase in life span with no tumor-free survivors. More than 1.0 log10 cell kill was observed at low microgram/kg doses in several human tumor models representing diverse histiotypes (CAKI-1 renal, LX-1 lung, HT-29 colon, LOX IMVI and UACC-62 melanomas, and MX-1 mammary). Less than 1.0 log10 cell kill was exhibited in other 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 administration, 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 the parent compound CC-1065. However, recovery of lost weight was not attained until 16-30 days posttherapy. Bizelesin was as active against murine leukemia sublines resistant to cisplatin, melphalan, and 1,3-bis-(2-chloroethyl)-1-nitrosourea as against the parental line but was totally inactive against a doxorubicin-resistant subline. The complete cross-resistance of the doxorubicin-resistant subline to bizelesin suggests that bizelesin may be a substrate for the efflux pump that causes multidrug resistance. Due to its breadth of antitumor activity, potency, unique mechanism of action, and lack of cross-resistance with other alkylating agents, bizelesin was selected for development in clinical trials by the National Cancer Institute and the Upjohn Company. Toxicological studies and pharmaceutical development have been completed, and clinical trials are planned to start in the summer of 1996.
Carter
C A
CA
Southern Research Institute, Birmingham, Alabama 35255-5305, USA.
Waud
W R
WR
Li
L H
LH
DeKoning
T F
TF
McGovren
J P
JP
Plowman
J
J
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D000080890:Duocarmycins; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D014183:Transplantation, Heterologous; D014508:Urea / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
D018906:Antineoplastic Agents, Alkylating; D000080890:Duocarmycins; D007211:Indoles; D014508:Urea; C072257:bizelesin