Dacarbazine

Absorption

Erratic, slow and incomplete.

Toxicity

LD50=350mg/kg (orally in mice)

Description

Dacarbazine is nevertheless considered the first representative of the series of triazene derivatives. It has been shown that it is an alkylating agent, and thus this drug inhibits RNA and protein synthesis to a greater degree than DNA. Dacarbazine is used intravenously for Hodgkin’s disease, soft-tissue sarcoma, and metastatic melanoma. A synonym of this drug is diticene.

Chemical properties

Off-white Cryst

Chemical properties

Dacarbazine is a white to ivory-colored crystalline solid.

The Uses of Dacarbazine

Dacarbazine is used as an antineoplastic for treatment of malignant melanoma and sarcomas.

The Uses of Dacarbazine

Used as an antineoplastic. Used in the treatment of malignant melanoma and sarcomas.

The Uses of Dacarbazine

progestogen

Background

An antineoplastic agent. It has significant activity against melanomas. (from Martindale, The Extra Pharmacopoeia, 31st ed, p564). Dacarbazine with Oblimersen is in clinical trials for the treatment of malignant melanoma.

Indications

For the treatment of metastatic malignant melanoma. In addition, dacarbazine is also indicated for Hodgkin's disease as a secondary-line therapy when used in combination with other antineoplastic agents.

What are the applications of Application

Dacarbazine is appears to exert cytotoxic effects

Definition

ChEBI: A monocarboxylic acid amide that is 1H-imidazole-4-carboxamide which is substituted at position 5 by a 3,3-dimethyltriaz-1-en-1-yl group. It is used for the treatment of metastatic malignant melanoma, and in combination with other drugs or the treatment of Hodgkin's disease and soft-tissue sarcoma.

Indications

Dacarbazine (DTIC-Dome) is activated by photodecomposition and by enzymatic N-demethylation. Eventual formation of a methyl carbonium ion results in methylation of DNA and RNA and inhibition of nucleic acid and protein synthesis. As with other alkylating agents, cells in all phases of the cell cycle are susceptible to dacarbazine.
The plasma half-life of dacarbazine is biphasic, with a distribution phase of 19 minutes and an elimination phase of 5 hours. The drug is not appreciably protein bound, and it does not enter the central nervous system (CNS). Urinary excretion of unchanged drug is by renal tubular secretion. Dacarbazine metabolism and decomposition is complex.
Dacarbazine is the most active agent used in metastatic melanoma, producing a 20% remission rate. It is also combined with doxorubicin and other agents in the treatment of various sarcomas and Hodgkin’s disease.
Dacarbazine may cause severe nausea and vomiting. Leukopenia and thrombocytopenia occur 2 weeks after treatment, with recovery by 3 to 4 weeks. Less common is a flulike syndrome of fever, myalgias, and malaise. Alopecia and transient abnormalities in renal and hepatic function also have been reported.

General Description

White to ivory microcrystals or off-white crystalline solid.

General Description

Dacarbazine is available in 100- and 200-mg vials for IVadministration in the treatment of Hodgkin’s disease, malignantmelanoma, carcinoid cancer, neuroblastoma, andsoft tissue sarcoma. Resistance to dacarbazine has been primarilyattributed to enhanced activity of AGAT. The volumeof distribution exceeds the amount of water in thebody suggesting the compound distributes into body tissuespossibly the liver. The agent is not highly protein bound(20%) and is metabolized in the liver by CYP to give MTICand 4-amino-5-imidazole-carboxamide (AIC).Thedemethylation reaction is mediated by isozymes CYP1A1/2and CYP2E1. Elimination occurs via the urine with 40% to50% occurring as unchanged drug. Dose-limiting myelosuppressionpresents as both leucopenia and thrombocytopenia.Other adverse effects include nausea, vomiting,flulike symptoms, photosensitivity, and pain at the injectionsite.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

Dacarbazine decomposes explosively at its melting point (250°C). Decomposes in the presence of light. Sensitive to oxidation.

Fire Hazard

Flash point data for Dacarbazine are not available. Dacarbazine is probably combustible.

Biochem/physiol Actions

Dacarbazine is a purine analog of naturally occurring purine precursor 5-amino-1H-imidazole-4-carboxamide (AIC). It is a synthetic triazine antineoplastic agent that exerts cytotoxic effects by acting as an alkylating agent and by inhibiting DNA synthesis and inducing apoptosis. It is known to induce hepatotoxicity in mice. Dacarbazine is not cell cycle-phase specific.

Pharmacokinetics

Dacarbazine is a synthetic analog of naturally occurring purine precursor 5-amino-1H-imidazole-4-carboxamide (AIC). After intravenous administration of dacarbazine, the volume of distribution exceeds total body water content suggesting localization in some body tissue, probably the liver. Its disappearance from the plasma is biphasic with initial half-life of 19 minutes and a terminal half-life of 5 hours. 1 In a patient with renal and hepatic dysfunctions, the half-lives were lengthened to 55 minutes and 7.2 hours. 1 The average cumulative excretion of unchanged DTIC in the urine is 40% of the injected dose in 6 hours. 1 DTIC is subject to renal tubular secretion rather than glomerular filtration. At therapeutic concentrations dacarbazine is not appreciably bound to human plasma protein.

Clinical Use

This DNA methylating agent is administered IV as a single agent in the treatment of malignant melanoma and in combination with other agents in the treatment of metastatic melanoma.

Side Effects

Approximately 40% of the drug is excreted unchanged, but both the 5-aminoimidazole-4-carboxamide (AIC, formed through the action of CYP1A enzymes) and the carboxylic acid (AIC hydrolysis product) are major urinary metabolites. Leukopenia and thrombocytopenia are the most common side effects and may be fatal. Patients also are at risk for hepatotoxicity, including hepatocellular necrosis.

Safety Profile

Confirmed carcinogen with experimental carcinogenic and tumorigenic data. Poison by intraperitoneal and parenteral routes. Moderately toxic by ingestion and intravenous routes. Experimental teratogenic effects. Human systemic effects by intravenous route: nausea or vomiting, leukopenia (reduced white blood cell count), and changes in dehydrogenase enzymatic activity. Mutation data reported. When heated to decomposition it emits toxic fumes of NOx.

Synthesis

Dacarbazine, 5-(3,3-dimethyl-1-triazeno)imidazol-4-carboxamide (30.6.5), is made by diazotation of 5-aminoimidazol-4-carboxamide with nitrous acid, which results in the formation of 5-diazoimidazol-4-carboxamide (30.6.4). Reacting this with dimethylamine gives the desired dacarbazine (30.6.5)

Potential Exposure

Dacarbazine is used in cancer chemo- therapy. Dacarbazine is used as an antineoplastic agent in the treatment of certain skin cancers, and is occasionally used in the therapy of other neoplastic diseases which have become resistant to alternative treatment.br Health professionals who handle this drug (for example, pharmacists, nurses, and physicians) may possibly be exposed during drug preparation, administration, or cleanup; however, the risks can be avoided through use of appropriate containment equipment and work practices .People receiving dacarbazine in treatment are also exposed.

Veterinary Drugs and Treatments

Dacarbazine has been used to treat relapsed canine lymphoma, soft tissue sarcomas and melanoma in dogs. In combination with doxorubicin, dacarbazine has been evaluated to treat dogs with relapsed lymphosarcoma. Ongoing studies evaluating various protocols are ongoing for this indication.

Drug interactions

Potentially hazardous interactions with other drugs
Aldesleukin: avoid concomitant use.
Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.

First aid

Skin Contact: Flood all areas of body thathave contacted the substance with water. Do not wait toremove contaminated clothing; do it under the water stream.Use soap to help assure removal. Isolate contaminatedclothing when removed to prevent contact by others. EyeContact: Remove any contact lenses at once. Flush eyeswell with copious quantities of water or normal saline for atleast 2030 min. Seek medical attention. Inhalation: Leavecontaminated area immediately; breathe fresh air. Properrespiratory protection must be supplied to any rescuers. Ifcoughing, difficult breathing or any other symptomsdevelop, seek medical attention at once, even if symptomsdevelop many hours after exposure. Ingestion: If convulsions are not present, give a glass or two of water or milk todilute the substance. Assure that the person’s airway isunobstructed and contact a hospital or poison center immediately for advice on whether or not to induce vomiting.

Environmental Fate

The exact mechanism of action of dacarbazine is unknown; however, several proposed mechanisms have been made including inhibition of DNA synthesis by acting as a purine analog, alkylating agent, and interference with sulfhydryl groups. It is most commonly classified as an alkylating agent in the triazene group. While the active compound of dacarbazine, DTIC, is structurally similar to purines, its primary mechanism of action precludes the agent from being classified as an antimetabolite. Dacarbazine is a synthetic compound that is metabolically activated to the active alkylating metabolite methyl-triazeno-imidazole-carboxamide (MTIC) via the cytochrome P450 system, primarily CYP1A1, CYP1A2, and CYP 2E1. MTIC is rapidly tautomerized into an inactive derivative, 5-aminoimidazole-4-carboxamide (AIC), which is renally excreted. The entire process of activating DTIC occurs within 15 min of intravenous infusion. DTIC exerts its actions throughout all phases of the cellular cycle. The antitumor effects of this compound are related to the induction of methyl adducts to DNA. The 70% of alkylation occurs at the N₇ position of guanine. The cytotoxic and mutagenic effects of MTIC are manifested through alkylation of DNA at the O₆ guanine position, accounting for 6–8% of methylated bases formed. This is primarily a result of generation of incorrect base pairing, leading to DNA double strand breaks and apoptosis.

Metabolism

Hepatic

Metabolism

Dacarbazine (DTIC) is assumed to be inactive. Dacarbazine is extensively metabolised in the liver by the cytochrome P450 isoenzymes CYP1A2 and CYP2E1 (and possibly in the tissues by CYP1A1) to its active metabolite 5-(3-methyl-triazen-1-yl)- imidazole-4-carboxamide (MTIC), which spontaneously decomposes to the major metabolite 5-amino-imidazole- 4-carboxamide (AIC). About half of a dose is excreted in the urine by tubular secretion; 50% as unchanged DTIC and approximately 50% as AIC.

storage

Color Code—Blue: Health Hazard/Poison: Storein a secure poison location. Prior to working with dacarbazine you should be trained on its proper handling and storage. Store in a refrigerator or a cool, dry place and protectfrom light. A regulated, marked area should be establishedwhere this chemical is stored in compliance with OSHAStandard 1910.1045.

Shipping

UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials.

Toxicity evaluation

Dacarbazine is a colorless to an ivory-colored crystalline solid that must be reconstituted and administered as a parenteral agent for intravenous injection. It is available as a dry powder in 100, 200, and 500mg vials that when reconstituted have a standard concentration of 10 mg dacarbazine per 1 ml solution and a pH of 3–4. Vials of dacarbazine should be refrigerated (2–8°C) and protected from light. When exposed to light, dacarbazine is rapidly decomposed to 4-diazoimidazole-5-carboxamide. When exposed to high temperatures (250–255°C) dacarbazine decomposes explosively. Dacarbazine is slightly soluble in water. Dacarbazine may be diluted in either normal saline or dextrose 5% water. Reconstituted solution is stable for 24 h at room temperature (20°C) and 96 h under refrigeration (4°C); however, it is recommended by the manufacturer to use the product within 8 and 72 h, respectively. Dacarbazine should not be used if it turns pink, as this is a sign of decomposition.

Incompatibilities

ncompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explo- sions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, and epoxides. Explosive decom- position reported @ 250℃ 255℃

Waste Disposal

It is inappropriate and possi- bly dangerous to the environment to dispose of expired or waste drugs and pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quanti- ties of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.