km-2210 and Neoplasms

Topics: Administration, Oral; Antibodies, Monoclonal; Chlorambucil; Estradiol; Estramustine; Humans; Neoplasms; Prednimustine; Receptors, Cell Surface

A phase I study was performed on a newly developed antitumor agent, Bestrabucil (KM 2210). The study was started at an initial dose of 1 n 25 mg/body, and gradually increased up to 32n 800 mg/body. With single (35 patients) and five-consecutive-day (36 patients) administration, the dose-limiting factor was found to be tarry stool, remarkable decrease in hemoglobin content, and strong nipple and breast pain. The maximum tolerated dose (MTD) was concluded to be around 700 to 800 mg/body. With long-term administration (the longest term, 20 weeks, 36 patients), the dose-limiting factor was concluded to be a decrease in the peripheral leukocyte count when the total amount administered reached about 10 g. Side effects on the alimentary system due to this agent, such as vomiting, nausea and anorexia, were observed. In addition, mastalgia and genital bleeding due to released estrogen were also seen, especially in the case of long-term administration.

Topics: Adult; Aged; Animals; Anorexia; Chlorambucil; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation; Estradiol; Female; Humans; Leukocyte Count; Leukopenia; Male; Middle Aged; Neoplasms; Pain; Rats

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.

Topics: Administration, Oral; Aged; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Division; Chlorambucil; Estradiol; Female; Humans; Male; Mice; Middle Aged; Neoplasms; Prostatic Neoplasms; Rats; Rats, Inbred Strains