Dacarbazine

Antineoplastic drug

Dacarbazine is a new type of purine precursor-class anticancer drug. It can interfere with purine biosynthesis, while having the role of alkylating agents together. It has inhibitory effects on mice sarcoma-180, lung cancer-755, melanoma B16 and leukemia L-1210. It takes effects on the G2 phase of the cell cycle with its main impact on RNA and protein synthesis, followed by DNA. Its oral absorption is not complete with large individual differences. After single-time intravenous injection, it reaches peak within 30 min and disappear after 6h. During the 6 h, the drug excreted from urine account for 30% of the total administered dose. It can’t penetrate through the blood-brain barrier.
Clinical cases mainly apply the citrate salt form of dacarbazine that appears as a white crystalline powder. Its aqueous solution exhibits strong acidicity with the pH being 1.9 to 2.3. It is mainly used for the treatment of malignant melanoma with a better efficacy than hydroxyurea. When being used in combination with vinblastine and BCNU, its efficacy can be improved. It can also be applied to the treatment of squamous cell carcinoma and undifferentiated carcinoma, leiomyosarcoma, fibrosarcoma and so on. However, it is ineffective in treating digestive tract tumors.

Pharmacodynamics

Dacarbazine is the structural analog of the precursor of the purine biosynthesis (see Figure 1), but with its biological effect being similar to the alkylating agent and belongs to the cell cycle non-specific drugs. It has inhibitory effects on several kinds of animal tumors with its major effects on in the G2 phase of the cell cycle with the inhibitory effect being more significant than RNA and protein synthesis.

Figure 1 the structural formula of dacarbazine.

Pharmacokinetics

Because of the incomplete oral absorption and being volatile, dacarbazine can only be subject to the intravenous administration. It first becomes mono-methyl form in the liver through N-demethylation and then metabolized into aminoimidazole carboxamide (AIC) and diazomethane. The active carbon ions are formed from the diazomethane. Dacarbazine has biphasic plasma declining with the half-life being 19 minutes and 5 hours, respectively. It is quickly removed from the tubular secretion. Within 6 hours, about 40% of it is discharged in its prototype form with the primary metabolite in urine being AIC.
This information is edited by Xiongfeng Dai from Chemicalbook

Clinical application

It has a better efficacy in treating the spread of malignant melanoma than other anti-cancer drugs. It is most commonly adopted of single-dose treatment and can also be used in combination with BCG, transfer factor and melphalan for immunochemical combination therapy. Applying (ABVD), (MOPP) with alternating method to some poor-outcome patients of advanced Hodgkin's disease can achieve long-term complete remission or even complete curing. It has certain efficacy in the treatment of various kinds of sarcomas, brain tumors, lung squamous cell carcinoma and small cell carcinoma, and children neuroblastoma.

Medicine interactions

1. When being used in combination with other drugs of bone marrow suppression, we should reduce the amount of this product.
2. When being used in combination with interleukin, the risk of allergic reactions will increase.
3. When applying this product to lively vaccines will increase the risk of infection caused by lively vaccines. Patients receiving immunosuppressive should not receive lively vaccines. Leukemia patient in remission period should at least stop three months before being subject to lively vaccines.
4. There is incompatibility when using dacarbazine in combination with hydrocortisone sodium succinate. Therefore, taking together is not suitable.

Side effects

1. Myelosuppression is often the major reason for limiting the dose with mainly affecting the white blood cells and platelets. The effect, compared with traditional mustard, occurs at relatively late time. Neutropenia often occurred in 10 days after treatment while thrombocytopenia occur in 10 to 15 days, but the last two can also be delayed to appear until after 2 to 4 weeks of the last treatment.
2. Nausea and vomiting often occur in 1 to 3 hours after administration with vomiting being sustainable to 12 hours. The side effects can occur in 90% of patients and can be very serious. Application of phenothiazines before medication may be invalid. Under rare circumstances, intractable nausea and vomiting make treatment must be stopped. Most patients can tolerate gradually, and these symptoms can be reduced within 1-2 days after the treatment.
3. It has been reported in patients subjected to dacarbazine of the emergence of a "flu-like" syndrome, including fever, muscle pain and fatigue. Other side effects include: injection site pain, facial flushing, abnormal feeling, hair loss and increased liver enzyme levels. There are also reports of liver necrosis. Dacarbazine is teratogenic and carcinogenic in animals. Allergies are relatively rare.
4. This drug can be put into FDA pregnancy category C.

Precautions

1. it has mutagenic or teratogenic effects. There may be carcinogenic and pregnant women should be disabled.
2. during the administration, the patients should stop breast-feeding.
3. Interference of the diagnostic agent: when using this product, there may be transient increases in the level of blood urea nitrogen, alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase.
4. Patients of varicella zoster should be disabled or should be prohibited for treatment of live virus vaccine.
5. Patients of renal dysfunction, infection should take with caution.
6. During the medication, the patients should be subject to monitoring of regular blood urea nitrogen, creatinine, uric acid, bilirubin, alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase.

Chemical Properties

It appears as slightly yellow crystalline powder with the M.p. being 205 ℃. It has also been reported of 250-255 ℃ (decomposition). It is easily soluble in acid, slightly soluble in methanol, ethanol but insoluble in water. It can be subject to decomposition when being exposed to heat, light and acid labile.

Uses

It belongs to antineoplastic agent. It is clinically used for the treatment of malignant melanoma with being effective in about 20-30% cases. Combination with vincristine and BCNU can further improve the efficacy. In addition, it also has certain efficacy in treating lung squamous cell carcinoma, sarcoma, leiomyosarcoma and fibrosarcoma but with poor efficacy in treating gastrointestinal cancer.

Production method

Take ethyl cyanoacetate as raw material, go through addition, amination, diazotization, coupling, reduction, formylation, cyclization, and, diazotization, condensation, through intermediate β-imino-β-ethoxy propionate hydrochloride, α-acetamide hydrochloride, α-amidino-α-phenylazo acetamide hydrochloride, 5-amino-imidazole-4-carboxamide hydrochloride to obtain it.

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.

Uses

progestogen

Uses

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

Uses

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

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

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.

General Description

White to ivory microcrystals or off-white crystalline solid.

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.

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

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.

Raw materials

Preparation Products