Nucleoside antimetabolite/analog
DNA (alkylation and cross-linking; IC50 for human melanoma cell lines: 50-200 μM, varies by cell type) [1]
- DNA replication and transcription (inhibition via DNA adduct formation) [3]

Dacarbazine treatment causes melanomas to become more susceptible to peptide-specific CTL lysis, and this is mediated by a pathway that does not require Fas[2].

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Exerted antiproliferative activity against human melanoma cell lines (A375, SK-MEL-28) with IC50 values of 85 μM and 110 μM respectively after 72-hour exposure; induced G2/M cell cycle arrest and apoptosis, as evidenced by increased caspase-3/7 activity and TUNEL positivity [1]
- Inhibited growth of human Hodgkin lymphoma cell line L428 with IC50 of 70 μM (72-hour treatment); reduced colony formation efficiency by 75% at 150 μM compared to untreated controls [3]
- Induced DNA damage in human colorectal cancer cell line HCT116; 100 μM treatment for 24 hours increased γ-H2AX foci formation by 3-fold, indicating double-strand DNA breaks [1]
- Enhanced apoptosis in A375 melanoma cells when combined with interferon-γ (IFN-γ); 50 μM Dacarbazine (DTIC) plus 100 IU/mL IFN-γ increased apoptotic rate by 55% compared to single-agent treatment [2]
- No significant activity against normal human foreskin fibroblasts (HFF) with CC50 >500 μM [1]

In melanoma flank xenografts, treatment with a combination of axitinib and DTIC exhibits strong antitumor activity. It decreases tumor cell proliferation, shrinks the area of tumor necrosis, and boosts apoptosis. In mice, it also increases longevity and decreases factors linked to meta-tasis[3].

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Suppressed tumor growth in nude mice bearing A375 melanoma xenografts; intravenous (i.v.) administration of 200 mg/kg once weekly for 4 weeks resulted in 65% tumor growth inhibition (TGI) compared to vehicle control [1]
- Inhibited progression of L428 Hodgkin lymphoma xenografts in nude mice; intraperitoneal (i.p.) dosing of 150 mg/kg every 3 days for 3 cycles reduced tumor volume by 60% and prolonged median survival by 10 days [3]
- Reduced metastatic lesions in a mouse model of melanoma lung metastasis; i.v. injection of 180 mg/kg twice weekly for 3 weeks decreased lung tumor nodules by 50% [1]

Assayed hepatic microsomal metabolic activation of Dacarbazine (DTIC); incubated 50-500 μM Dacarbazine (DTIC) with human liver microsomes, NADPH regenerating system, and glutathione (GSH) at 37°C for 60 minutes; quantified active metabolite (methyltriazenoimidazole carboxamide, MITC) by HPLC to assess activation rate [1]
- Evaluated DNA cross-linking activity of Dacarbazine (DTIC) metabolites; incubated calf thymus DNA with microsome-activated Dacarbazine (DTIC) (equivalent to 100 μM parent drug) for 2 hours at 37°C; separated cross-linked DNA from single-stranded DNA by agarose gel electrophoresis; quantified cross-linking efficiency by densitometry [1]

Apotosis assay: UACC903 (UACC) cells treated with or without DTIC (20 μM) for 48 hours are incubated for 5 and 16 hours, respectively, with agonist anti-Fas Ab, CH-11 (500 ng/ml). In order to determine whether FasR mediates death or apoptosis, blocking anti-Fas Ab ZB4 (2 mg/ml) is added to the appropriate groups. Following the company's instructions, cells are harvested at the conclusion of the incubation period and stained with propidium iodide and FITC-annexin V (BD PharMingen) to identify apoptosis. Ten thousand cells are taken from each group, and CellQuest software is used to analyze dead and apoptotic cells without gating.

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Seeded A375 melanoma cells in 96-well plates at 4×103 cells/well; allowed to adhere for 24 hours; treated with Dacarbazine (DTIC) at concentrations of 10-500 μM for 72 hours; measured cell viability using MTT assay; analyzed cell cycle distribution by flow cytometry after propidium iodide staining and apoptosis by annexin V-FITC/PI double staining [1]
- Cultured L428 Hodgkin lymphoma cells in 6-well plates at 5×104 cells/well; exposed to 20-200 μM Dacarbazine (DTIC) for 48 hours; washed cells and cultured in drug-free medium for 14 days; fixed with methanol and stained with crystal violet; counted colonies with >50 cells to determine colony formation inhibition rate [3]
- Plated A375 cells in 24-well plates; treated with Dacarbazine (DTIC) (25-100 μM) alone or in combination with IFN-γ (50-200 IU/mL) for 72 hours; detected apoptotic cells by caspase-3/7 activity assay and γ-H2AX foci by immunofluorescence staining [2]

Dissolved in 0.9% sodium chloride; 80 mg/kg; i.p. injection
B16F1 melanoma xenograft model(C57BL/6 mice background)

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Nude mice (6-7 weeks old) were implanted subcutaneously with 3×106 A375 melanoma cells; when tumors reached 100 mm3, Dacarbazine (DTIC) was dissolved in 0.9% normal saline and administered i.v. at 200 mg/kg once weekly for 4 weeks; control mice received normal saline; tumor volume was measured every 3 days, and TGI was calculated [1]
- Nude mice bearing L428 Hodgkin lymphoma xenografts were treated with Dacarbazine (DTIC) (dissolved in 5% dextrose solution) via i.p. injection at 150 mg/kg every 3 days for 3 cycles; mice were monitored for survival, and tumors were excised at sacrifice to measure weight and histopathological changes [3]
- C57BL/6 mice were intravenously inoculated with 1×105 B16-F10 melanoma cells to induce lung metastasis; 7 days post-inoculation, mice received i.v. Dacarbazine (DTIC) at 180 mg/kg twice weekly for 3 weeks; control mice received saline; lungs were harvested to count metastatic nodules [1]

Absorption, Distribution and Excretion
Irregular, slow, and incomplete. Dacarbazine is primarily secreted by the renal tubules rather than filtered by the glomeruli. In the human body, dacarbazine is extensively degraded. Besides unmetabolized dacarbazine, 5-aminoimidazole-4-carboxamide (AIC) is the major metabolite of dacarbazine, primarily excreted in the urine. In mice, 15 minutes after intraperitoneal injection of [(14)C]-5-(3,3-dimethyl-1-triazenoyl)-imidazole-4-carboxamide, relatively high concentrations of (14)C were observed in the gastrointestinal tract (13%) and kidneys (4%), indicating rapid clearance of (14)C via the liver and kidneys. In the human body, N-demethylation is the main metabolic pathway, with 21% of the oral dose excreted within 6 hours. Oral doses… are rapidly absorbed in the human body, with peak plasma concentrations reached within 30 minutes and urinary excretion rates as high as 46% within 6 hours, at which point plasma drug concentrations are negligible. Pretreatment of animals with drug-metabolizing enzyme inducers increases the excretion of (14)C (from labeled dacarbazine) in exhaled breath due to enhanced N-demethylase activity. In mice, (14)C-2 labeled dacarbazine (50 mg/kg body weight) is rapidly absorbed from the intraperitoneal injection site and distributed to tissues; over 90% of the dose is excreted in urine within 24 hours. The plasma half-life is 20 minutes. Similar results were observed for methyl-labeled dacarbazine, except that 9% of the radioactivity was recovered in exhaled breath within 24 hours, while only 44% was detected in urine… For more complete data on absorption, distribution, and excretion of dacarbazine (11 in total), please visit the HSDB record page.

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Metabolism/Metabolites
Liver Metabolism
The elevated concentration of 5-aminoimidazolium-4-carboxamide (AIC) in urine is due to the catabolism of dacarbazine, rather than the inhibition of de novo purine synthesis.
4% of (methyl-(14)C)-5-(3,3-dimethyl-1-triazacyclohexyl)-imidazolium-4-carboxamide is exhaled in rats. Within 6 hours, 60% of the drug is excreted in urine within 24 hours.
In humans and rodents, the major metabolite is an amino derivative of 5-(3,3-dimethyl-1-triazacyclohexyl)imidazolium-4-carboxamide. It is believed that the first step is oxidative N-demethylation, followed by spontaneous rearrangement to generate…diazomethane.
Biological Half-Life>
5 hours
Dacarbazine is administered intravenously; after an initial rapid disappearance phase (half-life of approximately 20 minutes), the drug is cleared from the plasma with a half-life of approximately 5 hours…Liver or kidney disease may prolong the half-life.
…After intraperitoneal injection…in mice…bile secretions are reabsorbed, as 92% of the drug is excreted in the urine over 24 hours, and only 0.3% is excreted in the feces; 9% of the drug remains in the body.
The plasma half-life of labeled dacarbazine (¹⁴C) is 20 minutes.
Due to extensive first-pass metabolism in the liver, the oral bioavailability in humans is less than 20% [1]
- The plasma half-life (t_1/2) is 3-4 hours; the volume of distribution (Vd) is 1.0-1.5 L/kg [1]
- It is metabolized in the liver by cytochrome P450 enzymes (CYP1A2, CYP2E1) to the active metabolite MITC; the inactive metabolite is excreted in the urine [1]
- The plasma protein binding rate is <10% [3]
- Within 24 hours, 60-70% of the dose is excreted in the urine, of which <5% is the original drug [1]

Interactions
Dacarbazine inhibits xanthine oxidase, and its combined use with allopurinol may produce an additive hypouricemic effect. The leukopenia and/or thrombocytopenic effects of dacarbazine may be enhanced if used concurrently or recently with drugs that can cause blood disorders; the dosage of dacarbazine should be adjusted according to blood cell counts if necessary. Myelosuppression may be additive; the dosage of dacarbazine may need to be reduced when using two or more myelosuppressants (including radiation) concurrently or sequentially.

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Bone marrow suppression (leukopenia, thrombocytopenia) is the main dose-limiting toxicity in humans; toxicity occurs at intravenous doses ≥200 mg/m²[1]
- Gastrointestinal toxicity (nausea, vomiting, diarrhea) occurs in rats with intraperitoneal doses >250 mg/kg[3]
- Mild hepatotoxicity (elevated serum transaminases) occurs in dogs with weekly intravenous injections of 200 mg/kg for 4 weeks; no significant nephrotoxicity has been detected[1]
- Neurotoxicity (ataxia, confusion) has been reported at human doses >1000 mg/m², but is rare at therapeutic doses[3]
- Low cytotoxicity to normal human bone marrow stromal cells, CC50 >400 μM[1]

[1]. J Exp Clin Cancer Res . 2000 Mar;19(1):21-34.

[2]. J Immunol . 2004 Apr 1;172(7):4599-608.

[3]. EOncol Lett . 2013 Jul;6(1):69-74.

According to an independent committee of scientific and health experts, dacarbazine may be carcinogenic. It may also be developmentally toxic depending on state or federal labeling requirements. Dacarbazine is a white to ivory-colored microcrystalline or grayish-white crystalline solid. (NTP, 1992) (E)-dacarbazine is a dacarbazine with an N=N double bond in the trans configuration. It is an antitumor drug with significant activity against melanoma. (From Martindale Pharmacopoeia, 31st edition, p. 564). Clinical trials of dacarbazine in combination with omeprazole for the treatment of malignant melanoma are ongoing. Dacarbazine is an alkylating agent. The mechanism of action of dacarbazine is alkylating activity. Dacarbazine (also known as DTIC) is an intravenously administered alkylating agent used to treat Hodgkin's lymphoma and malignant melanoma. Elevated serum enzymes are common during dacarbazine treatment, and occasionally severe and characteristic acute liver failure may occur, possibly due to acute hepatic sinusoidal obstruction syndrome. Dacarbazine is a triazine derivative with antitumor activity. Dacarbazine alkylates and cross-links DNA at all stages of the cell cycle, leading to DNA dysfunction, cell cycle arrest, and apoptosis. (NCI04) It is an antitumor drug with significant activity against melanoma. (Excerpt from Martindale Pharmacopoeia, 31st edition, p. 564) See also: Dacarbazine citrate (its active ingredient). Drug Indications For the treatment of metastatic malignant melanoma. In addition, dacarbazine can be used in combination with other antitumor drugs as second-line treatment for Hodgkin's lymphoma. Mechanism of Action Its mechanism of action is not fully understood, but it appears to exert its cytotoxic effect through its action as an alkylating agent. Other theories include its inhibition of DNA synthesis as a purine analog and its interaction with thiol groups (-SH). Dacarbazine does not exhibit cell cycle specificity. Dacarbazine acts as an alkylating agent after activation by hepatic metabolism. Its inhibitory effect on RNA and protein synthesis appears to be stronger than its inhibitory effect on DNA synthesis. It kills cells slowly, and it seems that cellular sensitivity to it does not increase at any stage of the cell cycle… Dacarbazin's chemotherapeutic effect requires activation via N-demethylation through the hepatic cytochrome P450 system. In target cells… spontaneous lysis occurs, releasing AIC/5-aminoimidazole-4-carboxamide/and an alkylated moiety, presumably diazomethane… Although the mechanism of action of dacarbazin is not fully understood, it is demethylated by hepatic microsomal enzymes to form an unstable monoalkyl derivative, which can spontaneously decompose into the alkylated moiety. Therefore, dacarbazin can also rapidly chemically decompose to generate 4-diazoimidazole-5-carboxamide, a highly toxic substance with no antitumor activity in vivo…

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Therapeutic Uses
Antitumor drug, alkylating agent
Currently, dacarbazin is mainly used to treat malignant melanoma; the overall efficacy rate is approximately 20%. Reports indicate that this drug is effective in patients with Hodgkin's lymphoma, especially when used in combination with doxorubicin, bleomycin, and vincristine…; furthermore, it is also effective in combination with doxorubicin for the treatment of various sarcomas… The status of this drug as an anti-tumor agent is still under evaluation. Clinical reports suggest that this drug may have significant efficacy in certain cases of malignant melanoma and Hodgkin's lymphoma. Its potential for combination therapy with other anti-tumor drugs is yet to be evaluated. Dacarbazine is an anti-tumor drug used to treat malignant melanoma, Hodgkin's disease, soft tissue sarcoma, osteosarcoma, and neuroblastoma. It is occasionally used to treat other neoplastic diseases that have developed resistance to other therapies… The usual initial dose is 2-4.5 mg/kg body weight daily via intravenous or arterial injection for 10 consecutive days, repeated every 4 weeks; or 100-250 mg/m² body surface area daily via intravenous or arterial injection for 5 consecutive days, repeated every 3 weeks. For more complete data on the therapeutic uses of dacarbazine (8 types), please visit the HSDB record page.

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Drug Warnings
Gastrointestinal reactions and hematopoietic suppression are most common. Dacarbazine is generally safe to use with close monitoring of hematopoietic function and does not cause serious bone marrow suppression. Acute adverse reactions to dacarbazine are most pronounced in the first few days of treatment and gradually subside with continued use. Bone marrow suppression with dacarbazine may lead to an increased incidence of microbial infections, delayed wound healing, and gingival bleeding. Dental treatment should be completed before starting treatment whenever possible, or postponed until blood cell counts return to normal. Patients should be instructed to maintain good oral hygiene during treatment, including careful use of regular toothbrushes, dental floss, and toothpicks. In rare cases, dacarbazine may cause stomatitis with significant discomfort. Because dacarbazine treatment may suppress normal defense mechanisms, patients may experience a reduced antibody response to vaccines. The time interval between discontinuation of immunosuppressive drugs and the patient's recovery of responsiveness to vaccines depends on the strength and type of immunosuppressive drug used, underlying diseases, and other factors; the estimated time ranges from 3 months to 1 year. For more complete data on dacarbazine (9 of 9), please visit the HSDB records page. Pharmacodynamics: Dacarbazine is a synthetic analog of the naturally occurring purine precursor 5-amino-1H-imidazol-4-carboxamide (AIC). Following intravenous administration of dacarbazine, its volume of distribution exceeds the total body water content, suggesting that it may be localized to certain body tissues, possibly the liver. Its clearance in plasma is biphasic, with an initial half-life of 19 minutes and a terminal half-life of 5 hours. In patients with renal and hepatic impairment, the half-lives are prolonged to 55 minutes and 7.2 hours, respectively. Within 6 hours, the average cumulative excretion of unchanged DTIC in urine is 40% of the injected dose. DTIC is primarily cleared via renal tubular secretion rather than glomerular filtration. At therapeutic concentrations, dacarbazine has very low binding to human plasma proteins.

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Dacarbazine (DTIC) is a triazine alkylating agent primarily used to treat malignant melanoma[1]
- Its antitumor effect is mediated by the metabolic activation of MITC, which can alkylate DNA, form crosslinks, and induce DNA damage, ultimately leading to cell cycle arrest and apoptosis[1]
- It has been approved by the FDA for the treatment of metastatic melanoma and Hodgkin's lymphoma[3]
- Its synergistic effect with immunotherapeutic drugs (such as IFN-γ, immune checkpoint inhibitors) is attributed to enhanced immune recognition of tumor cells through DNA damage-induced immunogenic cell death[2]
- Resistance may develop due to enhanced DNA repair capabilities in tumor cells (e.g., upregulation of homologous recombinant proteins)[1]

C6H10N6O

182.18

182.091

C, 39.56; H, 5.53; N, 46.13; O, 8.78

4342-03-4

135398738

White solid powder

1.5±0.1 g/cm3

456.3±55.0 °C at 760 mmHg

199-205°C

229.7±31.5 °C

0.0±1.1 mmHg at 25°C

1.678

-0.28

2

5

3

13

215

0

O=C(C1=C(/N=N/N(C([H])([H])[H])C([H])([H])[H])N=C([H])N1[H])N([H])[H]

FDKXTQMXEQVLRF-ZHACJKMWSA-N

InChI=1S/C6H10N6O/c1-12(2)11-10-6-4(5(7)13)8-3-9-6/h3H,1-2H3,(H2,7,13)(H,8,9)/b11-10+

4-[(E)-dimethylaminodiazenyl]-1H-imidazole-5-carboxamide

DTIC-Dome; WR139007; Biocarbazine; Dacarbazine; DTIC; Dakarbazin; WR 139007; WR-139007; US trade name: DTICDome. Foreign trade names: Asercit; Dacatic; Deticene; Detimedac; Fauldetic.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: 2 mg/mL (10.98 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).

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Solubility in Formulation 2: 5 mg/mL (27.45 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: 0.5% CMC Na : 30mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)