에스트라디올비스[4-[비스(2-클로로에틸)아미노]벤젠아세테이트]

Insoluble (NTP, 1992)

Soluble in dimethyl sulphoxide and N,N-dimethylformamide, but addition of water causes precipitation; soluble in benzene, chloroform, ethyl acetate, and 2-methoxyethanol.

Insoluble in water

104 to 149 °F (freeze dried) (NTP, 1992)

40-65 °C (freeze dried)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992)

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=22966-79-6]

Oestradiol mustard

Group 3: Not classifiable as to its carcinogenicity to humans

Volume 9: (1975) Some Aziridines, N-, S- and O-Mustards and Selenium

1987

1987

Estradiol mustard

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Male and female A/He mice, 6-8 weeks old, received 8 or 12 ip injections of estradiol mustard in tricaprylin at three dose levels (total doses, 1.6, 1.2 and 0.48 g/kg body weight). Two series of controls were maintained: untreated mice killed at the same time as the treated animals, and controls which received the vehicle alone. The experiments were terminated 24 weeks after the first injection, and the numbers of treated mice surviving were 19/20, 19/20 and 15/20 at the three dose levels, respectively. Lung tumors developed in 19/19, 19/19 and 11/15 mice with 5, 3.6 and 2.8 lung tumors per mouse. Of 77 males and 77 females injected with tricaprylin alone and surviving 24 weeks, 28% males and 20% females developed lung tumors, with 0.24 and 0.2 lung tumors per mouse. In the same experiment estradiol mustard was reported to be about 25 times less potent than uracil mustard on a molar basis.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Daily doses of 20-80 mg/kg body weight estradiol mustard given to dogs for 14 days produced vomiting, lymphopenia and reversible anemia at lower doses, and, in addition to these symptoms, convulsions, death and neutropenia at the highest dose. Female dogs showed signs of estrus and endometrial hyperplasia; degenerative changes in spermatogenic cells and squamous metaplasia of the prostate were observed in males.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Estradiol mustard (NSC 112259) was subcutaneously injected to female Sprague-Dawley-rats in weekly doses of 10 and 20 mg/kg up to a total dose (Dmax) of 500 or 760 mg/kg, respectively. Treatments reduced significantly the mean survival time. No carcinogenic properties were observed. Most of the estrogen mustard treated animals died from ovarian abscesses or peritonitis following pyometras. Toxic injuries were attributed to the chronical estrogenic stimulus.

/SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

A bioassay of the experimental anticancer drug estradiol mustard for possible carcinogenicity was conducted by administering the chemical by gavage to Sprague-Dawley rats and B6C3F1 mice. Groups of 35 rats and 34-36 mice of each sex were administered estradiol mustard at one of the following doses, either 0.62 or 1.25 mg/kg body weight for rats and either 15 or 30 mg/kg body weight for mice. The vehicle used for the test chemical consisted of 0.05% polysorbate 80 in phosphate-buffered saline. The rats and mice were dosed three times per week for 52 weeks, then observed for an additional 30-34 weeks. Controls consisted of groups of 10 rats and 15 mice of each sex that were not administered the chemical (untreated controls) and also of groups of 10 rats of each sex, 14 male mice, and 16 female mice administered the vehicle alone (vehicle controls). Pooled controls were also used. All surviving rats were killed at 84-86 weeks and all surviving mice at 82-86 weeks. Mean body weights of male rats and male and female mice administered estradiol mustard were lower throughout the greater part of the study than those of corresponding vehicle or untreated controls; mean body weights of dosed female rats were unaffected. Administration of the test chemical had no significant effect on the survival of either male or female rats. A large number of dosed mice died prior to the end of the study. The numbers of dosed male mice which were at risk as long as 52 weeks were sufficient, however, for development of tumors appearing up to that time. Time-adjusted analysis and life-table analyses were applied to data obtained with the mice. In rats, no tumors were observed in a statistically significant incidence in the animals administered estradiol mustard. In mice, lymphoma or lymphocytic leukemia occurred at significant incidences in low-dose (P=0.018) and high-dose (P<0.001) groups of males compared with those in the pooled vehicle controls (controls 0/28, low-dose 6/32, high-dose 17/29) and at significant incidences in low-dose (P=0.020) and high-dose (P=0.002) groups of females compared with those in the corresponding vehicle controls (controls 0/14, low-dose 9/30, high-dose 11/23). In addition, the incidences of lymphoma were statistically significant for dose-related trend for both the males (P<0.001) and the females (P=0.003). Since lymphoma was observed in male mice as early as 25 weeks, life-table analyses of the incidence in each sex were performed. The results indicated a dose association (P=0.001) between the administration of estradiol mustard and the time of observation of lymphoma in either sex of mice. In mice, alveolar/bronchiolar adenoma or carcinoma occurred at a significant incidence (P=0.004) in the low-dose group of males compared with the pooled vehicle controls (controls 2/28, low-dose 12/30, high-dose 5/24) and at a significant incidence (P=0.022) in the low-dose group of females compared with the pooled vehicle controls (controls 1/28, low-dose 7/27, high-dose 1/18). Sarcoma of the myocardium similarly occurred at a significant incidence (P=0.015) in the low-dose group of males compared with the pooled vehicle controls (controls 0/28, low-dose 6/30, high-dose 2/24) and at a significant incidence (P=0.002) in the low-dose group of females compared with the pooled vehicle controls (controls 0/28, low-dose 8/27, high-dose 1/12). The survival of both high-dose males and high-dose females was slightly lower than that of the respective low-dose groups and may account for the higher numbers of pulmonary tumors and myocardial sarcomas among low-dose mice of both sexes. The association of myocardial sarcoma with administration of the chemical in both dosed groups of each sex is strengthened by the fact that these tumors of the myocardium have not occurred in the more than 500 male and 500 female historical-control mice of this strain at the laboratory. Squamous cell carcinoma of the stomach occurred in the dosed male mice (high-dose 2/29) and in the dosed female mice (low-dose 2/26, high-dose 2/14) but was absent in all controls. Although the incidences in this bioassay were too low to be statistically significant, the fact that no squamous-cell carcinomas of the stomach have occurred in the more than 500 male and 500 female historical-control mice of this strain at this laboratory indicates that these gastric tumors were related to the administration of the estradiol mustard. It is concluded that under the conditions of this bioassay, estradiol mustard administered in a buffered saline vehicle was not carcinogenic in Sprague-Dawley rats. Estradiol mustard was carcinogenic in both male and female B6C3F1 mice, inducing lymphoma, sarcoma of the myocardium, alveolar adenoma or carcinoma, and squamous-cell carcinoma of the stomach.

Steroidal alkylating agents are supposed to bind to steroid hormone receptors in target tissues. By this interaction the steroid portion might act as a carrier for the alkylating group. Three steroidal agents (phenesterin, estradiol mustard, dehydroepiandrosterone mustard) were tested for their capacity to combine with estrogen and androgen receptors in normal and malignant target tissues. For measuring steroid receptor complexes ager gel electrophoresis was used. All three compounds (added at a 10(3)-fold excess) revealed in vitro no competition to receptor sites (estrogen and androgen binding). After preincubation of intact tissue estrogen mustard was effective in inhibiting the binding of 3H-estradiol and dehydroepiandrosterone mustard reduced the uptake of 3H-5alpha-DHT. This may be due to liberating of estradiol and dehydroepiandrosterone, respectively, from the intact molecule. From these data it is unlikely that the cytostatic steroidal agents are more effective than other alkylating drugs.

Estramustine phosphate (0.01 to 0.5 mM), an estradiol mustard derivative used in the therapy of prostatic carcinoma, inhibited the assembly of brain microtubules proteins in vitro and disassembled preformed microtubules. In the presence of estramustine phosphate, the minimum microtubule-protein concentration sufficient for the assembly of microtubules was increased. Low concentrations of taxol (20 microM) completely reversed the inhibition of assembly by estramustine phosphate. The effects were specific to estramustine phosphate since neither estradiol 17 beta-phosphate, the hormonal moiety of the drug, nor nornitrogen mustard, the alkylating moiety, had any effect on assembly. Estramustine phosphate (0.1 to 0.5 mM) was also found to reversibly inhibit fast axonal transport in the frog sciatic nerve. The nerve content of adenosine triphosphate, adenosine diphosphate, and adenosine monophosphate was not significantly affected by estramustine phosphate. Our results suggest that the cytotoxic action of estramustine phosphate could be dependent partially on an interaction with microtubules, probably via the microtubule-associated proteins.

The effects of the following cancer chemotherapeutic agents on serum hormonal levels, estrous cycles, and endocrine organs were studied in mature, normal Sprague-Dawley rats by radioimmunoassay, vaginal smear examination, and organ weight end point: estradiol mustard (NSC 112259), testosterone mustard (NSC 112260), phenoestrin (NSC 104469), methotrexate (NSC 740), 5-fluorouracil (NSC 19893), vinblastine (NSC 49842), vincristine (NSC 67574), nitrogen mustard (NSC 762), and 1,3-bis(2-chloroethyl)-1-nitrosourea (NSC 409962). Following 2 weeks of treatment, estradiol-17beta levels were markedly elevated by all compounds except testosterone mustard and nitrogen mustard, which caused a decrease. Estrone levels were elevated by methotrexate, 5-fluorouracil, vinblastine, vincristine, nitrogen mustard, and 1,3-bis(2-chloroethyl)-1-nitrosourea, but were lowered by estradiol mustard. Progesterone levels were elevated only by estradiol mustard and testosterone mustard and were not affected by other compounds. Prolactin surge during proestrus was suppressed by phenesterin and methotrexate. Luteinizing hormone levels were lowered by methotrexate and nitrogen mustard. Estrous cycles of rats treated with estradiol mustard were arrested at proestrus, and the uterine and pituitary weights of these rats markedly increased. Uterine weight loss was significant following treatment with testosterone mustard, 5-fluorouracil, and nitrogen mustard. Thyroid weight was reduced by all compounds except methotrexate and vinblastine. Significant increases in pituitary weights occurred following treatment with all compounds except 1,3-bis(2-chloroethyl)-1-nitrosourea. The effects on ovarian and adrenal weights were minimal although significant by some compounds. Thus, in addition to their direct antitumor effects, these agents also produced changes in endocrine system which may be synergistic or antagonistic to the chemotherapy of endocrine-responsive neoplasms.

Estramustine phosphate, an estradiol-mustard conjugate, was shown to reversibly inhibit a stage during the first hour of productive adenovirus 2 infection of HeLa cells. This drug, employed in the therapy of advanced prostatic cancer, specifically interacts with microtubule-associated proteins (MAPs) of the cytoskeleton. The results obtained under physiological conditions in vivo suggest a MAPs-interference with the microtubule-mediated vectorial migration of the virus inoculum to the nucleus. Virus attachment, uncoating kinetics and the appearance of established uncoating intermediates were not affected.

Estradiol mustard (EM) is the 3,17beta-diester of estradiol-17beta (E2) with the nitrogen mustard derivative chlorphenacyl. The ability of EM to bind to cytoplasmic estrogen receptors was tested by inhibition of the binding of 3H-E2 to rat uterine cytosol at 18 degrees C and 30 degrees C. At both temperatures an inhibition curve was observed in the presence of a large excess of drug, suggesting that the latter has a very weak binding affinity (100,000 times lower than E2). Incubation of uterine cytosol with increasing amounts of 3H-E2 in the presence and absence of an excess of EM indicated that the drug interacted with the receptors at the same sites as E2 (competitive inhibition). Preincubation of uterine cytosol at 18 degrees C with EM induced a progressive reduction of 3H-E2 binding capacity. This reduction also occurred, although to a lesser extent, when long-term incubation of the cytosol with EM was performed in the presence of labelled E2 from the start. The process was faster at 18 degrees C than at 4 degrees C and did not occur with EM preincubated in homogenization buffer. Exchange assays by 3H-E2 of uterine receptors preincubated with labelled E2 and excess EM indicated that the drug-induced inhibition of binding capacity was reversible and produced no apparent alteration of the receptors. Furthermore, the rate of exchange was similar to that observed with receptors previously filled with unlabelled E2. In 9 "receptor-positive" cytosols from human breast cancers, time-course study of the binding of 3H-E2 in the presence of excess of EM yielded similar results as those obtained with rat uterine cytosol. These results show that EM has a very low binding affinity for the extrogen receptors and that it is metabolized into one or several compounds of higher binding affinity. They suggest that EM is probably not significantly concentrated by the estrogen target tissues such as mammary cancers. Therefore, the drug is unlikely to be very valuable in the treatment of breast cancer through a specific mechanism involving concentration by the estrogen receptors.