Antitumor activity and pharmacokinetics of estra-1,3,5 (10)-triene-3,17 beta-diol, 3-benzoate, 17-((4-(4-bis(2-chloroethyl)amino)phenyl)-1-oxobutoxy) acetate) (Bestrabucil) in human tumor xenografts serially transplanted into nude mice.

Bestrabucil (KM2210), the benzoate of an estradiol-chlorambucil conjugate, was used experimental cancer chemotherapy against 13 human tumor xenografts serially transplanted into nude mice, and its pharmacokinetics was studied. The tumors were one esophageal, two gastric, six colon, one cholecystic and three breast carcinomas. Two tumor tissue fragments approximately 3 X 3 X 3 mm were inoculated into BALB/cA nude mice, which were then treated with KM2210 at doses of 100, 200 and 300 mg/kg/day orally starting 24 hr after the transplantation or when the tumor reached a weight of 100-300 mg. The concentration of KM2210 and its derivatives in the tumor xenografts, normal muscular tissue and blood were assayed by high performance liquid chromatography. Six out of 13 xenografts were found to be sensitive to KM2210. The concentrations of KM2210 and its derivatives in the tumor tissues of the sensitive xenografts were five to 10 times higher than those in blood and muscular tissue, and the antitumor activity correlated well with the area under the curve of active metabolites of KM2210 in the tumor.