km-2210 and Breast-Neoplasms

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Division; Chlorambucil; Drug Screening Assays, Antitumor; Estradiol; Estramustine; Humans; Receptors, Estrogen; Tumor Cells, Cultured

We investigated the effects of a benzoate of an estradiol-chlorambucil conjugate (KM2210) and chlorambucil on growth, estrogen receptor, and secretion of transforming growth factor (TGF)-alpha in the hormone-dependent human breast cancer cell line MCF-7. In the presence of 10(-10)-10(-6) M KM2210, the estrogen-induced growth of MCF-7 was completely inhibited. Inhibited growth of MCF-7 treated with 10(-8) or 10(-6) M KM2210 for 4 days was not rescued by removal of the drug and the addition of estradiol. By treatment of MCF-7 with KM2210 for 4 days, estrogen receptor-binding sites were decreased at 10(-8) M and were not detected at 10(-6) M but were unaltered by 10(-8) M chlorambucil. Moreover, estrogen receptor immunoreactivity and the level of estrogen receptor mRNA were decreased through treatment with 10(-6) M KM2210 for 4 days. These suppressions occurred prior to the onset of inhibitory action on MCF-7 growth. Secretion of TGF-alpha from MCF-7 was decreased by 4 days of treatment with 10(-8) and 10(-6) M KM2210 but not with chlorambucil. The addition of exogenous TGF-alpha generally restored the growth of MCF-7 treated with 10(-8) M KM2210. We concluded that KM2210 has irreversible or at least long-standing inhibitory effect on estrogen-dependent growth of MCF-7. It is conceivable that the decrease of estrogen receptor renders the cell unable to respond to estrogen with increased TGF-alpha secretion and succeeding cell growth.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Division; Chlorambucil; Drug Screening Assays, Antitumor; Estradiol; Humans; Receptors, Estrogen; Transforming Growth Factor alpha; Tumor Cells, Cultured

Three human breast carcinoma xenografts, MCF-7, R-27 and T-61 serially transplanted into nude mice were treated with mitomycin C (MMC) alone, KM2210 (estra-1, 3, 5(10)-triene-3, 17 beta-diol, 3 benzoate 17-[4-(4-bis(2-chloroethyl)amino)phenyl)-1-oxobutoxy)acetate) alone and KM2210 followed by MMC. One hundred or 300 mg of KM2210 per kg were administered orally daily from Day 1 to 4 and MMC at the dose of 3 mg/kg was given ip on Day 5. The antitumor activity of MMC on these xenografts was enhanced by pretreatment with KM2210, suggesting a new combination chemo- and endocrine therapy of hormone-dependent human breast carcinomas.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chlorambucil; Estradiol; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Mitomycin; Mitomycins; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Transplantation, Heterologous

A 37-year-old female, who had undergone a left standard mastectomy in May, 1983 for breast cancer, was treated with Tamoxifen and FT-207 postoperatively. The patient had no further evidence of disease until two and one-half years later, when a routine chest film showed a single, half-rounded density 6.5 cm in diameter in the hilus of her left lung. Bestrabucil, the benzoate of an estradiol-chlorambucil conjugate, was administered p.o. at a daily dose of 200 mg for four weeks. Thereafter, the tumor greatly decreased in size to 3.0 cm in diameter. When a left upper lobectomy was performed, the tumor was found to be necrotic tissue. Microscopically, a small cancer nest similar to the primary breast carcinoma was observed in the center of the necrosis. The necrotic tissue was surrounded with cellular infiltrate, markedly consisting of histiocytes.

Topics: Adenocarcinoma; Adult; Breast Neoplasms; Chlorambucil; Drug Evaluation; Estradiol; Female; Humans; Lung Neoplasms

Two cases of recurrent breast carcinoma were treated with KM2210 in an early phase II study conducted at our institute and complete response (CR) was obtained. Case 1, a 64-year-old woman, developed a reddish tumor at the mastectomy wound 3 years after the first operation. Two hundred milligrams of KM2210 per day was given p.o. and the tumor diminished completely within 4 wk after the initial treatment. This CR state has continued for 2 years and 4 months until the present time. Although leukopenia of less than 3,000/mm3 was observed several times during the treatment, counts of white cells recovered after the dose of KM2210 had been reduced. Case 2, a 61-year-old woman, noticed swelling of the left supraclavicular lymphnodes, one of which was confirmed to be metastatic duct cell carcinoma histologically 4 years after standard radical mastectomy. The residual two lymphnodes returned completely to normal within 4 wk after the initial administration of KM2210 at a dose of 100 mg/day p.o. This CR continued for 9 months until a new lesion was found in the same region. No adverse effects of the regimen were observed in this case. As KM2210 was shown to produce two CR cases in this early phase II study against recurrent breast carcinoma with few adverse effects, the further clinical application of this agent against breast carcinoma should be investigated.

Topics: Adenocarcinoma; Breast Neoplasms; Carcinoma, Papillary; Chlorambucil; Drug Combinations; Drug Evaluation; Estradiol; Female; Humans; Middle Aged; Neoplasm Recurrence, Local

We administered Bestrabucil, a benzoate ester of a complex of beta-estradiol and chlorambucil, continuously to six patients with breast cancer recurrent to local and regional lymph nodes, at a dose level of 200 mg/day. Of these six cases, one achieved CR, two PR, one MR, and two were NC. The drug was thus effective in 50% of the cases, with mild side effects. At the same time, since the concentration transfer to lymph nodes was satisfactory, Bestrabucil was thought to be an effective drug for the treatment of locally recurrent breast cancer.

Topics: Adult; Antineoplastic Agents; Breast Neoplasms; Chlorambucil; Drug Evaluation; Estradiol; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Recurrence

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