Disease relevance of dacarbazine

• Adjuvant dacarbazine in cutaneous melanoma [1].
• Case report: development of Hodgkin's disease in patient receiving long-term administration of dacarbazine and interleukin-2 for metastatic melanoma [2].
• Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: a Southwest Oncology Group study [3].
• Successful treatment of metastatic glucagonoma with dacarbazine [4].
• After one course of dacarbazine therapy, she had remission of the glucagonoma clinically with regression of tumor metastases as defined by liver scanning [5].

High impact information on dacarbazine

• We randomly assigned 117 patients with metastatic malignant melanoma to treatment with dacarbazine alone or dacarbazine in combination with tamoxifen [6].
• Dacarbazine and outpatient interleukin-2 in treatment of metastatic malignant melanoma: phase II Southwest Oncology Group trial [7].
• Patients were randomly assigned to receive either bolus therapy with doxorubicin at a dose of 60 mg/m2 and dacarbazine at a dose of 750 mg/m2 intravenously on day 1 (118 patients) or infusional therapy with doxorubicin at 60 mg/m2 and dacarbazine at 750 mg/m2 delivered by continuous intravenous infusion for 96 hours on days 1-4 (122 patients) [3].
• In chemotherapy experiments, the survival time of rats given left ventricular injections of LOX cells increased in a dose-dependent manner after the animals were treated with dacarbazine [8].
• Cell-mediated cytotoxic response in vitro to a Moloney strain of murine leukemia virus-induced tumor (LSTRA) altered by 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC) was investigated with the use of mixed-leukocyte tumor cell cultures (MLTC) [9].

Chemical compound and disease context of dacarbazine

• High-dose cisplatin and dacarbazine in the treatment of metastatic melanoma [10].
• Forty-three adult patients with locally advanced or metastatic soft tissue sarcoma entered a pilot study of combination chemotherapy comprising 50 mg of doxorubicin/m2 by intravenous bolus, 850 mg of dacarbazine/m2 by 1-hour infusion, and 5 g of ifosfamide/m2 by 24-hour infusion with mesna uroprotection [11].
• Fifty-five consecutive patients with advanced recurrent Hodgkin's disease resistant to MOPP chemotherapy (mechlorethamine, vincristine, procarbazine, and prednisone) were given ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine) [12].
• Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine [13].
• Hepatic vascular toxicity of dacarbazine (DTIC): not a rare complication [14].

Biological context of dacarbazine

• By day 5, daily doses of 1.7 mg/kg and higher led to a median 40% decrease in BCL2 protein in melanoma samples compared with baseline, concomitantly with increased tumour-cell apoptosis, which was greatly increased after dacarbazine treatment [15].
• We conclude that dacarbazine damages DNA only in cells which are synthesizing new DNA [16].
• Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine [17].
• The lack of biotransformation in these in vitro assays precludes the meaningful assessment of several major chemotherapeutic agents, including dacarbazine and cyclophosphamide [18].
• In vivo, no alkylation could be observed with 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide; however, the existence of naturally occurring S-methylcysteine in the rat hemoglobin may have overshadowed small increases in alkylation arising from exposure to this compound [19].

Anatomical context of dacarbazine

• Studies were conducted of proliferative stimulation of syngeneic lymphocytes and the generation of cytotoxic lymphocytes (CL's) in a mixed lymphocyte-tumor cell culture system by 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC)-induced antigens in L1210 and EL4 leukemia sublines [20].
• RESULTS: The dacarbazine-resistant cell lines SB2-D and MeWo-D exhibited increased tumor growth and metastatic behavior in vivo [21].
• Previous in vitro studies with azathioprine, monocrotaline, and dacarbazine suggested that toxins that cause HVOD initially causing HVOD target sinusoidal endothelial cells (SEC) perhaps via profound glutathione (GSH) depletion [22].
• The addition of B-cell lymphoma 2 (Bcl-2) antisense to dacarbazine in the treatment of metastatic melanoma demonstrates improved response rates and progression-free survival when compared with dacarbazine alone [23].
• Phase I trial of dacarbazine with cyclophosphamide, carmustine, etoposide, and autologous stem-cell transplantation in patients with lymphoma and multiple myeloma [24].

Associations of dacarbazine with other chemical compounds

• MEASUREMENTS AND MAIN RESULTS: Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine produced a complete and partial response rate of 57% (median duration, 21 months; range, 7 to more than 34) [13].
• In this phase III trial, we compared the effects of chemotherapy (cisplatin, vinblastine, and dacarbazine [CVD]) with those of sequential biochemotherapy consisting of CVD plus interleukin-2 and interferon alfa-2b [25].
• When the probabilities of complete remission and disease-free survival were reduced for SC, similar to the clinical expectation of SC after a seven- or eight-drug regimen like MOPP/doxorubicin, bleomycin, and vinblastine with or without dacarbazine (MOPP/ABV[D]), ABMT in first relapse was the preferred strategy and provided 6 additional months [26].
• The combination of TAM with DDP was highly synergistic as demonstrated by median effect analysis, whereas TAM was antagonistic with carmustine and an activated form of dacarbazine [27].
• From 1978 to 1982, selected "poor-risk" advanced-stage patients received nitrogen mustard, vincristine, procarbazine, prednisone plus Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), bleomycin, vinblastine, and dacarbazine (MOPP-ABVD) induction chemotherapy, while the remaining patients were randomized between MVVPP and MOPP [28].

Gene context of dacarbazine

• We propose that combination treatment with anti-VEGF/IL-8 or MEK inhibitors may potentiate the therapeutic effects of dacarbazine [21].
• Chemo-immunotherapy in patients with metastatic melanoma using sequential treatment with dacarbazine and recombinant human interleukin-2: evaluation of hematologic and immunologic parameters and correlation with clinical response [29].
• The aim of this study was to assess whether combined evaluation of O6-methylguanine methyltransferase (MGMT) and hMLH1 status determines sensitivity to monofuntional alkylating agents such as N-methyl-N-nitrosourea (MNU) and dacarbazine (DTIC) against gallbladder carcinoma cells [30].
• In a retrospective study, the expression levels of the MMR proteins, hMSH2, hMSH6 and hMLH1, were analysed by immunohistochemistry in melanoma metastases from 64 patients, who had received dacarbazine (DTIC) based chemotherapy [31].
• Mgmt-deficient cells are hypersensitive to the killing action of dacarbazine [32].

Analytical, diagnostic and therapeutic context of dacarbazine

• Two weeks later, patients received dacarbazine (1,200 mg/m2) chemotherapy [33].
• Alternating adoptive immunotherapy and dacarbazine chemotherapy appear to be reasonably tolerated by patients, but the response rate is not clearly better than that achieved with other rIL-2 regimens or with chemotherapy alone [33].
• Antisense oligonucleotides (ASO) targeted against BCL2 mRNA decreased BCL2 protein concentrations, increased tumour-cell apoptosis, and led to tumour responses in a mouse xenotransplantation model when combined with systemic dacarbazine [15].
• INTERVENTIONS: After optimization of antihypertensive therapy, patients received cyclophosphamide, 750 mg/m2 body surface area on day 1; vincristine, 1.4 mg/m2 on day 1, and dacarbazine, 600 mg/m2 on days 1 and 2, every 21 days [13].
• It offers a reasonable alternative to high-dose regimens, such as high-dose biochemotherapy or rIL-2 requiring prolonged periods of hospitalization, or single agent outpatient regimens, such as dacarbazine, which is usually not effective in patients with M1c disease [34].

References