Dacarbazine

Dacarbazine, an antineoplastic chemotherapy drug used in the treatment of various cancers, among them malignant melanoma, Hodgkin lymphoma, sarcoma, and islet cell carcinoma of the pancreas. Dacarbazine is also a member of the class of alkylating agents, which destroy cancer cells by adding an alkyl group (CnH2n+1) to its DNA.[1] The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring.Cancer cells are more sensitive to DNA damage than normal cells, because its proliferate faster and with less error-correcting than healthy cells, but alkylating antineoplastic agent are also toxic to normal cells (cytotoxic), leading to damage, in particular in cells that divide frequently, as those in the gastrointestinal tract, bone marrow, testicles and ovaries.[2]
Dacarbazine is commonly used as a single agent in the treatment of metastatic melanoma in middle of 2006, and as part of the ABVD chemotherapy regimen to treat Hodgkin lymphoma, and in the MAID regimen for sarcoma.Currently, Dacarbazine combined with Oblimersen for the treatment of malignant melanoma in clinical trials.[3]Dacarbazine is normally administered by injection (a shot) or intravenous infusion (IV) under the immediate supervision of a doctor or nurse.Now in phase III about Melanoma Recurrent 2015 March.
References:1. "Alkylating Agents". US National Library of Medicine. Retrieved 2 August 2014.
2. Wiedemann GJ. et al. "Ifosfamide, carboplatin and etoposide (ICE) combined with 41.8 degrees C whole body hyperthermia in patients with refractory sarcoma". European Journal of Cancer 1996,32A (5): 888–92.
3. MedLine, U.S. National Institutes of Health, National Library of Medicine.
4. CClinicalTrials.gov Identifier:NCT02288897.

Patient-derived solitary fibrous tumour xenografts predict high sensitivity to doxorubicin/dacarbazine combination confirmed in the clinic and highlight the potential effectiveness of trabectedin or eribulin against this tumour.[Pubmed:28284173]

Eur J Cancer. 2017 May;76:84-92.

BACKGROUND: Preclinical models that mimic pathological and molecular features of solitary fibrous tumour (SFT) represent an important tool to select effective regimes and novel compounds to be tested in the clinic. This study was aimed at developing two preclinical models of SFT, assessing their predictive value in the clinic and selecting potential novel effective treatments. MATERIAL AND METHODS: Two dedifferentiated-SFT (D-SFT) models obtained from patients' biopsies were grown in immunodeficient mice. The antitumour activity on these models of doxorubicin, Dacarbazine (DTIC), ifosfamide (monotherapy or combination), trabectedin and eribulin was tested. Twelve SFT patients were treated with doxorubicin and DTIC. Response by RECIST, progression-free survival and overall survival were retrospectively evaluated, distinguishing malignant-SFT (M-SFT) and D-SFT. RESULTS: Two D-SFT patient-derived xenografts (PDXs) that represent the first available preclinical in vivo models of SFT were developed and characterised. Doxorubicin/DTIC, DTIC/ifosfamide, doxorubicin/ifosfamide combinations consistently induced better antitumour activity than the single-agents. Particularly, doxorubicin/DTIC combination caused a max tumour volume inhibition >80% in both models. Doxorubicin/DTIC combo showed activity also in the case-series. Best RECIST responses were: 6 responses (M-SFT = 2 of 7, D-SFT = 4 of 5), 1 stable disease, 5 progressions, with a 6-month median progression-free survival (M-SFT = 6, D-SFT = 10 months). The PDXs were very sensitive to trabectedin and eribulin. CONCLUSION: Doxorubicin plus DTIC combination was effective in our two D-SFT mice models and appeared to be active also in the clinic, especially in high-grade D-SFT patients. Among additional drugs tested in the PDXs, trabectedin and eribulin were highly effective, providing a rational to test these drugs in D-SFT patients.

Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial.[Pubmed:28284557]

Lancet Oncol. 2017 Apr;18(4):435-445.

BACKGROUND: There are no established therapies specific for NRAS-mutant melanoma despite the emergence of immunotherapy. We aimed to assess the efficacy and safety of the MEK inhibitor binimetinib versus that of Dacarbazine in patients with advanced NRAS-mutant melanoma. METHODS: NEMO is an ongoing, randomised, open-label phase 3 study done at 118 hospitals in 26 countries. Patients with advanced, unresectable, American Joint Committee on Cancer stage IIIC or stage IV NRAS-mutant melanoma who were previously untreated or had progressed on or after previous immunotherapy were randomised (2:1) to receive either binimetinib 45 mg orally twice daily or Dacarbazine 1000 mg/m(2) intravenously every 3 weeks. Randomisation was stratified by stage, performance status, and previous immunotherapy. The primary endpoint was progression-free survival assessed by blinded central review in the intention-to-treat population. Safety analyses were done in the safety population, consisting of all patients who received at least one study drug dose and one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01763164 and with EudraCT, number 2012-003593-51. FINDINGS: Between Aug 19, 2013, and April 28, 2015, 402 patients were enrolled and randomly assigned, 269 to binimetinib and 133 to Dacarbazine. Median follow-up was 1.7 months (IQR 1.4-4.1). Median progression-free survival was 2.8 months (95% CI 2.8-3.6) in the binimetinib group and 1.5 months (1.5-1.7) in the Dacarbazine group (hazard ratio 0.62 [95% CI 0.47-0.80]; one-sided p<0.001). Grade 3-4 adverse events seen in at least 5% of patients the safety population in either group were increased creatine phosphokinase (52 [19%] of 269 patients in the binimetinib group vs none of 114 in the Dacarbazine group), hypertension (20 [7%] vs two [2%]), anaemia (five [2%] vs six [5%]), and neutropenia (two [1%] vs ten [9%]). Serious adverse events (all grades) occurred in 91 (34%) patients in the binimetinib group and 25 (22%) patients in the Dacarbazine group. INTERPRETATION: Binimetinib improved progression-free survival compared with Dacarbazine and was tolerable. Binimetinib might represent a new treatment option for patients with NRAS-mutant melanoma after failure of immunotherapy. FUNDING: Array BioPharma and Novartis Pharmaceuticals Corporation.

Examining the In Vitro Efficacy of the IAP Antagonist Birinapant as a Single Agent or in Combination With Dacarbazine to Induce Melanoma Cell Death.[Pubmed:28337955]

Oncol Res. 2017 Nov 2;25(9):1489-1494.

Antagonists of inhibitors of apoptosis proteins (IAPs), alone or in combination with genotoxic therapeutics, have been shown to efficiently induce cell death in various solid tumors. The IAP antagonist birinapant is currently being tested in phase II clinical trials. We herein aimed to investigate the antitumor efficacy of Dacarbazine in vitro, both as a single agent and in combination with birinapant, in melanoma cell lines. Covering clinically relevant drug concentration ranges, we conducted a total of 5,400 measurements in a panel of 12 human melanoma cell lines representing different stages of disease progression. Surprisingly, functionally relevant synergies or response potentiation in combination treatments was not observed, and only one cell line modestly responded to birinapant single treatment (approximately 16% cell death). Although we did not study the underlying resistance mechanisms or more complex in vivo scenarios in which Dacarbazine/birinapant response synergies may still possibly manifest, our findings are nevertheless noteworthy because IAP antagonists were demonstrated to strongly enhance responses to DNA-damaging agents in cell lines of other cancer types under comparable experimental conditions in vitro.