km-2210 and Prostatic-Neoplasms

Tumor oriented anticancer agents with estrogen as a carrier have been extensively studied since 1950's. Only Estracyt and bestrabucil have been evaluated to be useful in clinical trials. Although the use of estrogen as a carrier for anticancer agents aimed at the development of the anticancer drug for the receptor mediated chemotherapy, these two drugs did not show any affinity to estrogen receptor. The history tells us that the development of anticancer agents for the estrogen receptor mediated chemotherapy is extremely difficult. Estracyt is reported to exert its anticancer effect on prostate cancer through the specific binding to the estramustine binding protein (EMBP) which is present only in the prostate gland and cancer. Bestrabucil shows the selective uptake by the various malignant cells and is indicated that bestrabucil exerts its anti-cancer effects on various malignant tumors including breast cancer and hematopoietic malignancy, through the affinity to malignant cells. The mechanism is unknown and to be elucidated.

Topics: Animals; Antineoplastic Agents; Carcinoma 256, Walker; Chlorambucil; Drug Carriers; Estradiol; Estramustine; Estrogens; Humans; Male; Prostatic Neoplasms; Rats

It is known that diffusible trophic factors play an important role in both the normal and cancerous growth regulatory processes of hormone-responsive cells such as are found in the prostate and mammary glands. Consequently, it is important to identify whether the production of such growth factors is affected by administration of therapeutic agents. We examined the effect of bestrabucil, a benzoate of an estradiol-chlorambucil conjugate, on the production of growth factor(s) by Shionogi carcinoma 115 (SC-115) cells, an androgen-responsive cultured cancer cell line. We then investigated whether the inhibitory effect found was specific to bestrabucil, or if it was also produced by a mixture of the 2 compounds, estradiol and chlorambucil. Bioassay employing BALB/3T3 cells demonstrated the presence of two kinds of growth factor in the conditioned medium obtained by culturing SC-115 cells in medium containing 10(-8) M testosterone; these factors could be separated by heparin-sepharose column chromatography using 0.5 M NaCl and 1.1 M NaCl. When the SC-115 cells were cultured in medium containing bestrabucil, at a concentration of 10(-5) M, no growth factor activity was detected in the fraction eluted from the heparin-sepharose column by 1.1 M NaCl. At bestrabucil concentrations of 10(-5)-10(-7) M, concentration-dependent inhibition of growth factor production by SC-115 cells could be demonstrated by 3H-thymidine uptake assay. However, this inhibitory effect could not be demonstrated using only a mixture of estradiol and chlorambucil.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Androgens; Animals; Antineoplastic Agents; Carcinoma; Cell Count; Chlorambucil; Culture Media, Conditioned; Estradiol; Growth Substances; Male; Mice; Mice, Inbred BALB C; Prostatic Neoplasms; Tumor Cells, Cultured

Serum and tissue concentrations of bestrabucil (KM 2210), a combined agent of 17-estradiol and Chlorambucil, were examined in patients with urogenital cancers including those of the kidney, bladder, prostate and testis. We administered orally 100mg (50 mg X 2/day of bestrabucil for 3 days), and determined its plasma levels and metabolites. A maximum drug concentration, i.e., 9.25 ng/ml, was noted 3 hours after administration; a constant plasma level of 5 ng/ml was maintained and the concentration of free chlorambucil was low. After single or consecutive oral administration of bestrabucil (100-300 mg), tumor specimens contained significantly large amounts of bestrabucil in comparison with adjacent normal tissue. Selective accumulation of the active component in tumor tissue suggests the clinical usefulness of bestrabucil.

Topics: Administration, Oral; Chlorambucil; Estradiol; Humans; Kidney Neoplasms; Male; Prostatic Neoplasms; Testicular Neoplasms; Urinary Bladder Neoplasms; Urogenital Neoplasms

KM 2210, a combination product of 17 beta-estradiol and chlorambucil, was administered to 15 patients with advanced (stage C and D) prostatic carcinoma. We studied the clinical efficacy and the drug concentration in the blood and prostatic tissues. The administered doses were 100 mg or 150 mg p.o., in 2 or 3 divided doses/day (or every other day in a few cases) for periods ranging from 30 to 369 days; the maximum total dose was 42.5 g. Objective clinical responses, according to the criteria by Shida et al., were observed in 6 (40%) patients. Side effects included gastrointestinal symptoms, e.g. loss of appetite or nausea, anemia and leukopenia. No obvious hepatic disorder was observed.

Topics: Aged; Animals; Child; Chlorambucil; Estradiol; Humans; Male; Middle Aged; Prostate; Prostatic Neoplasms; 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