Nucleoside antimetabolite/analog

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].

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.

Absorption, Distribution and Excretion
Erratic, slow and incomplete.
Dacarbazine is subject to renal tubular secretion rather than glomerular filtration. In man, dacarbazine is extensively degraded. Besides unchanged dacarbazine, 5-aminoimidazole -4 carboxamide (AIC) is a major metabolite of dacarbazine excreted in the urine.
15 MIN AFTER IP INJECTION OF [(14)C]-5-(3,3-DIMETHYL-1- TRIAZENO)-IMIDAZOLE-4-CARBOXAMIDE TO MICE, LEVELS OF (14)C WERE RELATIVELY HIGH IN GI TRACT (13%) & KIDNEYS (4%), INDICATING RAPID HEPATIC & RENAL ELIMINATION OF (14)C.
IN MAN, N-DEMETHYLATION WAS MAJOR METABOLIC PATHWAY, & 21% OF ORAL DOSE...WAS EXCRETED IN EXPIRED AIR IN 6 HR. THAT ORAL DOSE...WAS READILY ABSORBED IN HUMAN PT WAS INDICATED BY PEAK PLASMA LEVELS OF DRUG IN 30 MIN & URINARY EXCRETION OF UP TO 46% IN 6 HR, WHEN PLASMA DRUG LEVELS WERE NEGLIGIBLE.
PRETREATMENT OF ANIMALS WITH INDUCERS OF DRUG-METABOLIZING ENZYMES INCR AMT OF (14)C /FROM LABELED DACARBAZINE/ EXCRETED IN EXPIRED AIR, OWING TO INCR N-DEMETHYLASE ACTIVITY.
In mice, ((14)C-2)-labelled dacarbazine (50 mg/kg bw) is rapidly absorbed from the site of its ip injection and distributed to tissues; and more than 90% of the dose is eliminated in the urine within 24 hours. The plasma half-life was 20 min. Studies with dacarbazine labelled at the methyl group gave similar results, except that 9% of the radioactivity was recovered in the expired air within 24 hours, and only 44% was found in the urine ... .
For more Absorption, Distribution and Excretion (Complete) data for DACARBAZINE (11 total), please visit the HSDB record page.

---

Metabolism / Metabolites
Hepatic
Elevated urinary concn of 5-aminoimidazole-4-carboxamide (AIC) are derived from the catabolism of dacarbazine, rather than by inhibition of de-novo purine biosynthesis.
RATS EXCRETED 4% OF (METHYL-(14)C)-5-(3,3-DIMETHYL-1-TRIAZENO)-IMIDAZOLE-4-CARBOXAMIDE IN EXPIRED AIR IN 6 HR & 60% IN URINE IN 24 HR.
IN MAN & IN RODENTS, MAJOR METABOLITE IS AMINO DERIV /OF 5-(3,3-DIMETHYL-1-TRIAZENO)IMIDAZOLE-4-CARBOXAMIDE/. IT IS BELIEVED THAT FIRST STEP IS OXIDATIVE N-DEMETHYLATION, FOLLOWED BY SPONTANEOUS REARRANGEMENT TO YIELD...DIAZOMETHANE

---

Biological Half-Life
5 hours
Dacarbazine is administered iv; after an initial rapid phase of disappearance (t/2 of about 20 minutes) the drug is removed from plasma with a half-time of about 5 hours ... The half-life is prolonged in the presence of hepatic or renal disease.
...AFTER IP INJECTION...TO MICE... BILIARY-SECRETED MATERIAL WAS REABSORBED, SINCE 92% WAS EXCRETED IN 24-HR URINE & ONLY 0.3% IN FECES; 9% WAS RETAINED IN BODY. PLASMA T/2 OF (14)C /IN LABELED DACARBAZINE/ WAS 20 MIN.

Interactions
Dacarbazine-induced inhibition of xanthine oxidase may cause additive hypouricemic effects when use concurrently with allopurinol.
Leukopenic and/or thrombocytopenic effects of dacarbazine may be increased with concurrent or recent therapy /with blood dyscrasia-causing medications/ if these medications cause the same effects; dosage adjustment of dacarbazine, if necessary, should be based on blood counts.
Additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively /with dacarbazine/.

[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.

Dacarbazine can cause cancer according to an independent committee of scientific and health experts. It can cause developmental toxicity according to state or federal government labeling requirements.
Dacarbazine appears as white to ivory microcrystals or off-white crystalline solid. (NTP, 1992)
(E)-dacarbazine is a dacarbazine in which the N=N double bond adopts a trans-configuration.
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.
Dacarbazine is an Alkylating Drug. The mechanism of action of dacarbazine is as an Alkylating Activity.
Dacarbazine (also known as DTIC) is an intravenously administered alkylating agent used in the therapy of Hodgkin disease and malignant melanoma. Dacarbazine therapy has been associated with serum enzyme elevations during therapy and occasional cases of severe and distinctive acute hepatic failure, probably caused by acute sinusoidal obstruction syndrome.
Dacarbazine is a triazene derivative with antineoplastic activity. Dacarbazine alkylates and cross-links DNA during all phases of the cell cycle, resulting in disruption of DNA function, cell cycle arrest, and apoptosis. (NCI04)
An antineoplastic agent. It has significant activity against melanomas. (from Martindale, The Extra Pharmacopoeia, 31st ed, p564)
See also: Dacarbazine citrate (is active moiety of).

---

Drug Indication
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.

---

Mechanism of Action
The mechanism of action is not known, but appears to exert cytotoxic effects via its action as an alkylating agent. Other theories include DNA synthesis inhibition by its action as a purine analog, and interaction with SH groups. Dacarbazine is not cell cycle-phase specific.
Dacarbazine functions as an alkylating agent after metabolic activation in the liver. It appears to inhibit the synthesis of RNA and protein more than it inhibits the synthesis of DNA. It kills cells slowly, and there appears to be no phase of the cell cycle in which sensitivity is increased ... .
...FOR CHEMOTHERAPEUTIC EFFECTIVENESS, DACARBAZINE REQUIRES INITIAL ACTIVATION BY CYTOCHROME P450 SYSTEM OF LIVER THROUGH N-DEMETHYLATION REACTION. IN TARGET CELL...OCCURS SPONTANEOUS CLEAVAGE LIBERATING AIC /5-AMINOIMIDAZOLE-4-CARBOXAMIDE/ & ALKYLATING MOIETY, PRESUMABLY DIAZOMETHANE...
Although the mechanism of action of dacarbazine is not known in detail, it is demethylated by liver microsomal enzymes to form an unstable monoalkyl derivative which can decompose spontaneously into alkylating moieties. In light, dacarbazine can also rapidly undergo chemical decomposition to form 4-diazoimidazole-5-carboxamide, which is highly toxic but which has no antitumor activity in vivo ... .

---

Therapeutic Uses
Antineoplastic Agents, Alkylating
AT PRESENT DACARBAZINE IS EMPLOYED PRINCIPALLY FOR THE TREATMENT OF MALIGNANT MELANOMA; THE OVERALL RESPONSE RATE IS ABOUT 20%. BENEFICIAL RESPONSES HAVE ALSO BEEN REPORTED IN PATIENTS WITH HODGKIN'S DISEASE, PARTICULARLY WHEN THE DRUG IS USED CONCURRENTLY WITH DOXORUBICIN, BLEOMYCIN, AND VINBLASTINE ..., AS WELL AS IN VARIOUS SARCOMAS WHEN USED WITH DOXORUBICIN ... .
...STATUS AS ANTINEOPLASTIC AGENT IS STILL UNDER EVALUATION. CLINICAL REPORTS INDICATE THAT AGENT MAY HAVE SIGNIFICANT ACTIVITY IN SOME CASES OF MALIGNANT MELANOMA & HODGKIN'S DISEASE. STILL TO BE ASSESSED IS POSSIBLE USE...IN COMBINATION WITH OTHER ANTINEOPLASTIC AGENTS.
Dacarbazine is used as an antineoplastic agent in the treatment of diseases such as malignant melanomas, Hodgkin's disease, soft-tissue sarcomas, osteogenic sarcomas, and neuroblastomas. It is occasionally used in the therapy of other neoplastic diseases that have become resistant to alternative treatment ... the usual initial dose is 2-4.5 mg/kg body weight intravenously or intra-arterially daily for 10 days and repeated after intervals of 4 weeks, or 100-250 mg/sq m of body surface for 5 days and repeated after intervals of 3 weeks.
For more Therapeutic Uses (Complete) data for DACARBAZINE (8 total), please visit the HSDB record page.

---

Drug Warnings
GI REACTIONS & HEMATOPOIETIC DEPRESSION ARE MOST PROMINENT. ... IF HEMATOPOIETIC ACTIVITY IS CAREFULLY MONITORED, DACARBAZINE USUALLY CAN BE ADMIN WITHOUT SERIOUS MYELOSUPPRESSIVE CONSEQUENCES.
ACUTE ADVERSE EFFECTS /OF DACARBAZINE/ ARE MOST PROMINENT DURING FIRST FEW DAYS OF TREATMENT & TEND TO SUBSIDE WITH CONTINUED ADMIN.
The bone marrow depressant effects of dacarbazine 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 during treatment, including caution in use of regular tooth brushes, dental floss, and toothpicks. Dacarbazine may also rarely cause stomatitis associated with considerable discomfort.
Because normal defense mechanisms may be suppressed by dacarbazine therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year.
For more Drug Warnings (Complete) data for DACARBAZINE (9 total), please visit the HSDB record page.

---

Pharmacodynamics
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.

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).

---

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.

---

View More

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

---

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