Amsacrine

393.46

393.46

257-094-3

00DPD30SOY

249992

DTXSID4022604

C240

Yellow crystalline powder

L - Antineoplastic and immunomodulating agents

2935009090

88.7

4

1.4±0.1 g/cm3

230-240 °C

563°C at 760 mmHg

294.3±32.9 °C

1.723

H2O: <1 mg/mL;CHC1 1.0 (mg/mL)

Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ) that bears appropriate label. An inventory should be kept, showing quantity of carcinogen & date it was acquired Facilities for dispensing should be contiguous to storage area.

Oral-mouse LD50: 53.42 mg/kg; intraperitoneal-mouse LD50: 15.47 mg/kg

Combustible; heat decomposes to release toxic nitrogen oxides and sulfur oxide fumes; drug side effects; nausea, vomiting, bone marrow lesions, etc.

193.1 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Mol wt 429.93. Crystals, mp 197-199 °C /Hydrochloride/|Mol wt 489.57. Crystals, mp 292-293 °C /Methanesulfonate/

III

6.1(b)

3249

Warehouse ventilated, low temperature and dry

Bulk: A sample stored at 60 °C for 30 days showed no decomposition (IR, TLC or UV). Solution: A sample was dissolved in methanol and diluted with water (1:33). No decomposition was detected by UV after standing 4 days at room temperature and exposed to light.

PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp & carcinogenic wastes generated by this treatment conducted to & burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols & thiosulfate. The reactivity of various alkylating agents varies greatly ... & is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness & safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/

/Amsacrine/... is incompatible with chloride or sulphate ions ... .

PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food & beverage containers or utensils, & the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, & rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes & wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth & purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care & vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... & when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, & contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) & label fixed to it, giving date of test & avg air-flow measured. This test should be repeated periodically & after any structural changes. /Chemical Carcinogens/|For more Preventive Measures (Complete) data for AMSACRINE (9 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped & will resist attack from the carcinogen. Both bottle & the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies & airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary & secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen & is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container & the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest & most secure form of transport & notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/

highly toxic

Symptoms of overdose include nausea and vomiting, diarrhea, some cardiotoxicity (rarely).

Leukopenic and/or thrombocytopenic effects of amsacrine may be increased with concurrent or recent therapy if these medications /blood dyscrasia-causing medications/ cause the same effects; dosage adjustment of amsacrine, if necessary, should be based on blood counts.|Additive bone marrow depression, including severe dermatitis and/or mucositis, may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively.

LD50 Mouse intraveneous 33.7 mg/kg|LD50 Dog oral 50 mg/kg|LD50 Mouse subcutaneous 110 mg/kg|LD50 Mouse intraperitoneal 15,470 ug/kg|LD50 Mouse oral 53,420 ug/kg

96-98%

For treatment of acute myeloid leukaemia.

Cytostatic agent with antiviral and immunosuppressive properties.|Amsacrine is indicated for induction of remission in acute adult leukemia refractory to conventional therapy. /Included in US product labeling/|118 patients with acute leukemias, including initial, relapsed and refractory cases, were treated with domestic Amsacrine (m-AMSA), singly or combined with other drugs. The total CR rate was 39.5% in ALL and 38.8% in ANLL, the response rate was 47.5% for both types of acute leukemias. The CR rate of relapsed and refractory ALL and ANLL treated with combination chemotherapy including domestic m-AMSA was 30.8% and 46.2% respectively. Domestic m-AMSA was similar to the foreign product and many other antitumor drugs in side effects and toxicity. The pharmacokinetics parameters of the drugs, C12h/C6h,K21 and Cmax were correlated with the therapeutic effectiveness|The synthetic aminoacridine derivative amsacrine (m-AMSA) is capable of preventing DNA from serving as a template in replication and DNA synthesis. This mechanism of action is similar to that of anthracyclines, but clinical evidence suggests the lack of cross-resistance. The recommended dosage in patients with solid tumors is 90-120 mg/sq m intravenously every 3-4 weeks. Despite the initial encouraging reports from experimental models, m-AMSA has shown no real impact in the treatment of patients with a wide variety of solid tumors. In relapsed acute nonlymphocytic leukemia, 20-30% of patients will achieve complete remission. An increased remission rate is obtained when m-AMSA is combined with other agents, especially with high-dose cytosine arabinoside, with a complete remission rate of 50-60% in relapsed patients. Currently, several phase III trials are evaluating m-AMSA combinations against daunorubicin-containing regimens in patients with previously untreated acute leukemia. The potential role of these regimens in this disease remains to be defined.|For more Therapeutic Uses (Complete) data for AMSACRINE (7 total), please visit the HSDB record page.

Human systemic effects by intravenous route: nausea or vomiting, thrombosis distant from the injection site, and bone marrow changes.|Although very little information is available regarding distribution of antineoplastic agents into breast milk, breast-feeding is not recommended during chemotherapy because of the potential risks to the infant (adverse effects, mutagenicity, carcinogenicity).|No information is available on the relationship of age to the effects of amsacrine in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require adjustment of dosage in patients receiving amsacrine.|The bone marrow depressant effects of amsacrine may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.|For more Drug Warnings (Complete) data for AMSACRINE (19 total), please visit the HSDB record page.

Amsacrine is an aminoacridine derivative that is a potent intercalating antineoplastic agent. It is effective in the treatment of acute leukemias and malignant lymphomas, but has poor activity in the treatment of solid tumors. It is frequently used in combination with other antineoplastic agents in chemotherapy protocols. It produces consistent but acceptable myelosuppression and cardiotoxic effects.

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)|Agents that are capable of inserting themselves between the successive bases in DNA, thus kinking, uncoiling or otherwise deforming it and therefore preventing its proper functioning. They are used in the study of DNA. (See all compounds classified as Intercalating Agents.)

Poorly absorbed|Volume of distribution (VolD) -- 1.67 L/kg. Amsacrine does not significantly penetrate into the CNS|Elimination: Renal: 35% of the dose is excreted by the kidneys within 72 hours after administration (20% as intact drug). Biliary: Amsacrine is also eliminated by biliary excretion.|In cancer patients, amsacrine undergoes biphasic elimination, with a distribution half-life of 0.25-1.6 hours and an elimination half-time of 4.7-9 hours. The total plasma clearance rate is 200-300 ml/min per sq m, and the apparent distribution volume is 70-110 l/sq m, suggesting concentration in tissues. During a 1 hour injusion of amasacrine at 90-200 mg/sq m, the peak plasma concentration was 10-15 umol/l.|Although not fully reported, early trials in which amsacrine was given orally failed to reach the maximum tolerated dose, as shown by lack of toxicity even at doses as high as 500 mg/sq m per day, suggesting incomplete or erratic absorption. In subsequent studies, the intravenous route was used, with which the maximum tolerated dose in patients with solid tumors is 100-150 mg/sq m when administered over 1-3 hours.|After intravenous administration of (14)C amsacrine to mice and rats, > 50% of the radiolabel was excreted in bile within the first 2 hours, and the bile:plasma ratio was > 400:1; 74% of an intravenous dose was excreted in the feces of mice with 72 hours. These studies demonstrate the importance of the liver in clearance of amsacrine.

Extensive, primarily hepatic, converted to glutathione conjugate.|Oxidative metabolism of the anti-cancer drug amsacrine 4'-(9-acridinylamino) methane-sulphan-m-anisidide has been suggested to account for its cytotoxicity. However, enzymes capable of oxidizing it in non-hepatic tissue have yet to be identified. A potential candidate, that may be relevant to the metabolism of amsacrine in blood and its action in myeloid leukaemias and myelosuppression, is the haem enzyme myeloperoxidase. We have found that the purified human enzyme oxidizes amsacrine to its quinone diimine, either directly or through the production of hypochlorous acid. In comparison, the 4-methyl-5-methylcarboxamide derivative of amsacrine, CI-921 9-[[2-methoxy-4[(methylsulphonyl)-amino]phenyl]amino)-N, 5-dimethyl-4-acridine carboxamide, reacted poorly with myeloperoxidase, although it was oxidized by hypochlorous acid. Detailed studies of the mechanism by which myeloperoxidase oxidizes amsacrine revealed that the semiquinone imine free radical is a likely intermediate in this reaction. Oxidation of amsacrine analogues indicated that factors other than their reduction potential determine how readily they are metabolized by myeloperoxidase. Both amsacrine and CI-921 inhibited production of hypochlorous acid by myeloperoxidase. CI-921 acted by trapping the enzyme as the inactive redox intermediate compound II. Amsacrine inhibited by a different mechanism that may involve conversion of myeloperoxidase to compound III, which is also unable to oxidize Cl-. The susceptibility of amsacrine to oxidation by myeloperoxidase indicates that this reaction may contribute to the cytotoxicity of amsacrine toward neutrophils, monocytes and their precursors.|In mouse bile, 5'- and 6'-glutathione conjugates were present in roughly equal amounts and accounted for 70% of the excreted biliary radiolabel after administration of radiolabelled amsacrine. In rats, the principal biliary metabolite was the 5'-gutathione conjugate, which accounted for 80% of the excreted radiolabel within the first 90 minutes and > 50% of the administered dose over 3 hours. The 6'-conjugate was also subsequently identified in rat bile. In rat liver microsomes and human neutrophils, intermediate oxidation products have been identified as N1'-methanesulfonyl-N4'-(9-acridinyl)-3'-methoxy-2',5'-cyclohexadience-1',4'-dii mine and 3'-methoxy-4'-(9-acridinylamino-2'5'-cyclohexadien-1'-one.

8-9 hours

Amsacrine binds to DNA through intercalation and external binding. It has a base specificity for A-T pairs. Rapidly dividing cells are two to four times more sensitive to amsacrine than are resting cells. Amsacrine appears to cleave DNA by inducing double stranded breaks. Amsacrine also targets and inhibits topoisomerase II. Cytotoxicity is greatest during the S phase of the cell cycle when topoisomerase levels are at a maximum.|Amsacrine binds to DNA through intercalation and external binding and has base specificity for A-T pairs. Cycling cells are two to four times more sensitive to amsacrine than are resting cells. Cells initially in S and G2 phases are grossly delayed in their capacity for normal progression, leading to an accumulation of cells in the S phase, followed at later times by arrest in the G2 phase.|Cytotoxicity of several classes of antitumor DNA intercalators is thought to result from disturbance of DNA metabolism following trapping of the nuclear enzyme DNA topoisomerase II as a covalent complex on DNA. Here, molecular interactions of the potent antitumor drug amsacrine (m-AMSA), an inhibitor of topoisomerase II, within living K562 cancer cells have been studied using surface-enhanced Raman (SER) spectroscopy. The work is based on data of the previously performed model SER experiments dealing with amsacrine/DNA, drug/topoisomerase II and drug/DNA/topoisomerase II complexes in aqueous buffer solutions. The SER data indicated two kinds of amsacrine interactions in the model complexes with topoisomerase II alone or within ternary complex: non-specific (via the acridine moiety) and specific to the enzyme conformation (via the side chain of the drug). These two types of interactions have been both revealed by the micro-SER spectra of amsacrine within living K562 cancer cells. Our data suppose the specific interactions of amsacrine with topoisomerase II via the side chain of the drug (particular feature of the drug/topoisomerase II and ternary complexes) to be crucial for its inhibitory activity.

Contact with skin: wash with soap and water.|/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/

/SPECIAL STUDIES/ It caused DNA double-strand breaks and DNA-protein cross-links ... in human cell lines at a concentration of about 1 umol/l. Amsacrine caused DNA breaks preferentially ... at a very specific site within the AML1 locus in several human cell lines.|/SPECIAL STUDIES/ Amsacrine caused chromosomal aberrations in ... HeLa cells and in cultured human peripheral blood lymphocytes. It also induced micronuclei in neonatal human lymphocytes. Fluorescence in-situ hybridization techniques revealed a high freqency of dicentrics and stable translocations in amsacrine-treated human peripheral blood lymphocytes. ... In one study, amsacrine caused chromosomal aberrations, but no sister chromatid exchange in blood lymphocytes of patients treated with this drug by intravenous infusion.

AMSA