Bestrabucil, the
benzoate of an
estradiol-
chlorambucil conjugate, was initially developed as a target-oriented
anticancer agent for breast
cancers with positive
estrogen receptors, by conjugating a tumoricidal agent,
chlorambucil, to a vehicle,
estradiol. Further studies, however, revealed that regardless of the presence of
estrogen receptors,
bestrabucil selectively accumulates in malignant
tumor cells. The unique feature of
bestrabucil, selective affinity to
tumor cells, was demonstrated in in vitro and in vivo studies. Significantly larger amounts of 3H-bestrabucil accumulated in malignant cells (3T3-SV40 transformed) than in normal cells (3T3). In vitro inhibition effects of
bestrabucil on cell growth was observed only in malignant cells. Selective accumulation of
bestrabucil in malignant
tumor tissues was also demonstrated in in vivo experiments. After a single
oral administration of 100 mg/kg of
bestrabucil to female Wistar rats bearing Walker 256
carcinoma,
bestrabucil accumulated significantly occurred in
tumor tissues with little or no accumulation in normal tissues and blood. Anti-
tumor effects and toxicities of
bestrabucil and
chlorambucil, were compared using Walker 256
carcinoma.
Bestrabucil exerted its antitumor effects with little change in leucocyte counts in the peripheral blood, whereas
chlorambucil showed significant side effects. Finally, selective accumulation of
bestrabucil in malignant
tumor tissues, was demonstrated clinically.
Tumor specimens obtained during the operation of patients with various types of
cancer, 24 hours after
oral administration of 100 mg of
bestrabucil, contained significantly larger amounts of
bestrabucil compared with adjacent normal tissues. Clinical trials of
bestrabucil are being carried out at present.
Bestrabucil seems to be a promising target-oriented
anticancer agent and deserves further investigation.