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Darinaparsin

Darinaparsin is a small-molecule organic arsenical with potential antineoplastic activity. Although the exact mechanism of action is unclear, darinaparsin, a highly toxic metabolic intermediate of inorganic arsenicals (iAs) that occurs in vivo, appears to generate volatile cytotoxic arsenic compounds when glutathione (GSH) concentrations are low. The arsenic compounds generated from darinaparsin disrupt mitochondrial bioenergetics, producing reactive oxygen species (ROS) and inducing ROS-mediated tumor cell apoptosis; in addition, this agent or its byproducts may initiate cell death by interrupting the G2/M phase of the cell cycle and may exhibit antiangiogenic effects. Compared to inorganic arsenic compounds such as arsenic trioxide (As2O3), darinaparsin appears to exhibit a wide therapeutic window. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

Highlights on recent research using darinaparsin

1. Darinaparsin: a novel organic arsenical with promising anticancer activity.

Darinaparsin is an organic arsenical composed of dimethylated arsenic linked to glutathione, and is being investigated for antitumor properties in vitro and in vivo. While other arsenicals, including arsenic trioxide, have been used clinically, none have shown significant activity in malignancies outside of acute promyelocytic leukemia. Darinaparsin has significant activity in a broad spectrum of hematologic and solid tumors in preclinical models. Here, we review the literature describing the signaling pathways and mechanisms of action of darinaparsin and compare them to mechanisms of cell death induced by arsenic trioxide. Darinaparsin has overlapping, but distinct, signaling mechanisms. We also review the current results of clinical trials with darinaparsin (both intravenous and oral formulations) that demonstrate significant antitumor activity. [source: Mann KK, Wallner B, Lossos IS, Miller WH Jr. Expert Opin Investig Drugs. 2009 Nov;18(11):1727-34.]

2. A phase I clinical trial of darinaparsin in patients with refractory solid tumors.

PURPOSE: Darinaparsin, an organic arsenic, targets essential cell survival pathways. We determined the dose-limiting toxicity (DLT) and maximum tolerated dose of darinaparsin in patients with advanced cancer. EXPERIMENTAL DESIGN: Patients with solid malignancies refractory to conventional therapies were treated with i.v. darinaparsin daily for 5 days every 4 weeks. The starting dose (78 mg/m(2)) escalated to 109, 153, 214, 300, 420, and 588 mg/m(2). A conventional "3 + 3" design was used. RESULTS: Forty patients (median age, 61.5 years; median number of prior therapies, 5) received therapy; 106 cycles were given (median, 2; range, 1-12). Twenty patients reported no drug-related toxicities. No DLTs were reported at a dose of <420 mg/m(2). At 588 mg/m(2), two of four patients developed DLTs, including grade 3 altered mental status and ataxia. Of four patients treated at the de-escalated dose of 500 mg/m(2), one developed similar toxicities. De-escalating the dose to 420 mg/m(2) (n = 8) resulted in two neurologic DLTs. Further de-escalation to 300 mg/m(2) (n = 3) resulted in no drug-related toxicities. Arsenic plasma levels peaked on treatment day 3, plateaued on day 5, and returned to baseline on day 7. Plasma levels varied within cohorts but increased with increasing doses. The median plasma arsenic half-life was 16.2 hours. Seven (17.5%) patients had stable disease for > or =4 months (median, 6; range, 4-11), including 4 of 17 with colorectal and 2 of 3 with renal cancer. CONCLUSIONS: The recommended dose for phase II trials is 300 mg/m(2) i.v. given daily for 5 days every 4 weeks. [source: Tsimberidou AM, Camacho LH, Verstovsek S, Ng C, Hong DS, Uehara CK, Gutierrez C, Daring S, Stevens J, Komarnitsky PB, Schwartz B, Kurzrock R. Clin Cancer Res. 2009 Jul 15;15(14):4769-76.]

3. Phase II study of darinaparsin in patients with advanced hepatocellular carcinoma.

BACKGROUND: Darinaparsin is a novel organic arsenic that reaches higher intracellular concentration with decreased toxicity compared to inorganic arsenic. We conducted a multi-center phase II study with darinaparsin in patients with advanced HCC. METHODS: Eligibility criteria included unresectable or metastatic measurable HCC, up to two prior systemic treatments, ECOG performance status < or = 2, Child Pugh Class A or B and adequate organ functions. Darinaparsin was administered at 420 mg/m(2) intravenously, twice weekly at least 72 h apart for 3 weeks in a 4-week cycle. The primary end point was response rate. A Simon two-stage design was used. RESULTS: Among 15 patients in the first stage, no objective responses were observed. Two patients had stable disease. The median number of cycles on study per patient was 2 (1-6). The median progression free survival and overall survival were 55 days (95% confidence interval: 50-59) and 190 days (95% confidence interval: 93-227), respectively. No treatment related hospitalizations or deaths occurred. Treatment related grade 1-2 toxicities included nausea, vomiting (26.7% each), fatigue (20%), anorexia and diarrhea (13.3% each). Grade 3 anorexia, wheezing, agitation, abdominal pain and SGPT were observed in 1 patient each (6.7%). One patient experienced grade 4 hypoglycemia (6.7%). CONCLUSIONS: Darinaparsin could be safely administered with tolerable toxicity profiles, and no QTc prolongation in patients with advanced HCC. However, at this dose and schedule, it has shown no objective responses in HCC and this trial was terminated as planned after the first stage of efficacy analysis. [source: Wu J, Henderson C, Feun L, Van Veldhuizen P, Gold P, Zheng H, Ryan T, Blaszkowsky LS, Chen H, Costa M, Rosenzweig B, Nierodzik M, Hochster H, Muggia F, Abbadessa G, Lewis J, Zhu AX. Invest New Drugs. 2010 Oct;28(5):670-6. Epub 2009 Jun 30.]

4. Chemical and clinical development of darinaparsin, a novel organic arsenic derivative.

The inorganic arsenic derivative arsenic trioxide (ATO) has proven to be highly efficacious in patients with acute promyelocytic leukemia (APL) and has been associated with complete cytogenetic response in most treated patients diagnosed with this disease. This is due to ATO's direct effect on PML-RARalpha oncoprotein patognomonic for APL. ATO has shown moderate activity against certain other hematologic and solid organ malignancies but is also associated with significant toxicities, especially when used at higher doses. The development of orally bioavailable organic arsenic derivatives (OAD) offering improved toxicity profiles and better efficacy may expand the use of arsenic derivatives in hematologic malignancies and solid tumors. The favorable in vivo carcinostatic activity of S-dimethylarsino-thioglucose, the first OAD synthesized in murine leukemia models by our group in 1975, set the stage for our efforts to develop OADs. Unfortunately, the program remained dormant for almost two decades. The success of ATO in APL in the late 1990s re-ignited the interest in the use of OADs in cancer chemotherapy. This review describes the chemical development of OADs and summarizes the clinical development of a promising lead compound, Darinaparsin (ZIO-101; SGLU; S-dimethylarsino-glutathione), for the treatment of a variety of cancers. [SOURCE: Quintás-Cardama A, Verstovsek S, Freireich E, Kantarjian H, Chen YW, Zingaro R. Anticancer Agents Med Chem. 2008 Dec;8(8):904-9.]

Current developer:    ZIOPHARM Oncology, Inc.

1. Wu, Jennifer; Henderson, Charles; Feun, Lynn; Veldhuizen, Peter; Gold, Philip; Zheng, Hui; Ryan, Theresa; Blaszkowsky, Lawrence S.; Chen, Hao-Bin; Costa, Max; Rosenzweig, Barry; Nierodzik, Mary Lynn; Hochster, Howard; Muggia, Franco; Abbadessa, Giovanni; Lewis, Jonathan; Zhu, Andrew X. Phase II study of darinaparsin in patients with advanced hepatocellular carcinoma. Investigational New Drugs (2010), 28(5), 670-676.

2. Schwartz, Brian Eric; Lewis, Jonathan; Komarnitsky, Philip B. Organoarsenic compounds and methods for the treatment of cancer. PCT Int. Appl. (2010), 44pp. CODEN: PIXXD2 WO 2010021928 A1 20100225 CAN 152:304068 AN 2010:238163

3. Rickles, Richard; Lee, Margaret S.  -Adrenergic receptor agonists for the treatment of B-cell proliferative disorders. PCT Int. Appl. (2009), 111 pp. CODEN: PIXXD2 WO 2009151569 A2 20091217 CAN 152:67621 AN 2009:1566750

4. Mann, Koren K.; Wallner, Barbara; Lossos, Izidore S.; Miller, Wilson H., Jr. Darinaparsin: a novel organic arsenical with promising anticancer activity. Expert Opinion on Investigational Drugs (2009), 18(11), 1727-1734. CODEN: EOIDER ISSN:1354-3784. CAN 152:66258 AN 2009:1368468

5. Tsimberidou, Apostolia Maria; Camacho, Luis H.; Verstovsek, Srdan; Ng, Chaan; Hong, David S.; Uehara, Cynthia K.; Gutierrez, Catalina; Daring, Shawn; Stevens, Jan; Komarnitsky, Philip B.; Schwartz, Brian; Kurzrock, Razelle. A Phase I Clinical Trial of Darinaparsin in Patients with Refractory Solid Tumors. Clinical Cancer Research (2009), 15(14), 4769-4776. CODEN: CCREF4 ISSN:1078-0432. CAN 152:230287 AN 2009:849678

6. Amedio, John C., Jr.; Waligora, Frank Walter. Preparation of arsenic compounds and their use for treatment of cancer. PCT Int. Appl. (2009), 34pp. CODEN: PIXXD2 WO 2009075870 A1 20090618 CAN 151:56982 AN 2009:741081

7. Diaz, Z.; Mann, K. K.; Marcoux, S.; Kourelis, M.; Colombo, M.; Komarnitsky, P. B.; Miller, W. H. A novel arsenical has antitumor activity toward As2O3-resistant and MRP1/ABCC1-overexpressing cell lines. [Erratum to document cited in CA150:365775]. Leukemia (2009), 23(2), 431. CODEN: LEUKED ISSN:0887-6924. CAN 150:555242 AN 2009:689208

8. Matulis, Shannon M.; Morales, Alejo A.; Yehiayan, Lucy; Croutch, Claire; Gutman, Delia; Cai, Yong; Lee, Kelvin P.; Boise, Lawrence H. Darinaparsin induces a unique cellular response and is active in an arsenic trioxide-resistant myeloma cell line. Molecular Cancer Therapeutics (2009), 8(5), 1197-1206. CODEN: MCTOCF ISSN:1535-7163. CAN 151:115927 AN 2009:635938

9. Campas, C.; Castaner, R. Darinaparsin: Organic arsenical apoptosis inducer oncolytic. Drugs of the Future (2009), 34(2), 97-100. CODEN: DRFUD4 ISSN:0377-8282. CAN 151:484474 AN 2009:601059

10. Wallner, Barbara P.; Komarnitsky, Philip B. Combination therapy with organic arsenicals for the treatment of cancer. PCT Int. Appl. (2009), 31pp. CODEN: PIXXD2 WO 2009061373 A1 20090514 CAN 150:506982 AN 2009:584243

11. Yamanaka, Kenzo; Kato, Koichi; Mizoi, Mutsumi; An, Yan; Nakanao, Masayuki; Hoshino, Mikio; Okada, Shoji. Dimethylarsine likely acts as a mouse-pulmonary tumor initiator via the production of dimethylarsine radical and/or its peroxy radical. Life Sciences (2009), 84(17-18), 627-633. CODEN: LIFSAK ISSN:0024-3205. CAN 151:441826 AN 2009:438898

12. Quintas-Cardama, Alfonso; Verstovsek, Srdan; Freireich, Emil; Kantarjian, Hagop; Chen, Yi Wen; Zingaro, Ralph. Chemical and clinical development of darinaparsin, a novel organic arsenic derivative. Anti-Cancer Agents in Medicinal Chemistry (2008), 8(8), 904-909. CODEN: AAMCE4 ISSN:1871-5206. CAN 150:343935 AN 2009:134325

13. Rickles, Richard; Lee, Margaret S. Use of adenosine A2A receptor agonists and phosphodiesterase (PDE) inhibitors for the treatment of B-cell proliferative disorders, and combinations with other agents. PCT Int. Appl. (2009), 70 pp. CODEN: PIXXD2 WO 2009011893 A2 20090122 CAN 150:160095 AN 2009:86451

14. Rickles, Richard; Pierce, Laura; Lee, Margaret S. Combinations for the treatment of B-cell proliferative disorders. PCT Int. Appl. (2009), 79pp. CODEN: PIXXD2 WO 2009011897 A1 20090122 CAN 150:160094 AN 2009:83374

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16. Diaz, Z.; Mann, K. K.; Marcoux, S.; Kourelis, M.; Colombo, M.; Komarnitsky, P. B.; Miller, W. H., Jr. A novel arsenical has antitumor activity toward As2O3-resistant and MRP1/ABCC1-overexpressing cell lines. Leukemia (2008), 22(10), 1853-1863. CODEN: LEUKED ISSN:0887-6924. CAN 150:365775 AN 2008:1245101

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18. Wallner, Barbara P.; Komarnitsky, Philip B. Method for controlling angiogenesis in animals. PCT Int. Appl. (2008), 65pp. CODEN: PIXXD2 WO 2008054594 A2 20080508 CAN 148:529491 AN 2008:555539

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20. Gutsch, Paul; Renzelmann, Brian. Preparation of arsenic derivatives for the treatment of cancer. PCT Int. Appl. (2007), 36pp. CODEN: PIXXD2 WO 2007027344 A2 20070308 CAN 146:302327 AN 2007:259905

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37. Wu Jennifer; Henderson Charles; Feun Lynn; Van Veldhuizen Peter; Gold Philip; Zheng Hui; Ryan Theresa; Blaszkowsky Lawrence S; Chen Haobin; Costa Max; Rosenzweig Barry; Nierodzik Marylynn; Hochster Howard; Muggia Franco; Abbadessa Giovanni; Lewis Jonathan; Zhu Andrew X Phase II study of darinaparsin in patients with advanced hepatocellular carcinoma. Investigational new drugs (2010), 28(5), 670-6. Journal code: 8309330. E-ISSN:1573-0646. PubMed ID 19565187 AN 2010669728 In-process for

38. Mann Koren K; Wallner Barbara; Lossos Izidore S; Miller Wilson H Jr Darinaparsin: a novel organic arsenical with promising anticancer activity. Expert opinion on investigational drugs (2009), 18(11), 1727-34. Journal code: 9434197. E-ISSN:1744-7658. PubMed ID 19780704 AN 2009737470

39. Tsimberidou Apostolia Maria; Camacho Luis H; Verstovsek Srdan; Ng Chaan; Hong David S; Uehara Cynthia K; Gutierrez Catalina; Daring Shawn; Stevens Jan; Komarnitsky Philip B; Schwartz Brian; Kurzrock Razelle A phase I clinical trial of darinaparsin in patients with refractory solid tumors. Clinical cancer research : an official journal of the American Association for Cancer Research (2009), 15(14), 4769-76. Journal code: 9502500. ISSN:1078-0432. PubMed ID 19584162 AN 2009486602

40. Tomillero A; Moral M A Gateways to clinical trials. Methods and findings in experimental and clinical pharmacology (2009), 31(2), 107-46. Journal code: 7909595. ISSN:0379-0355. PubMed ID 19455266 AN 2009356977

41. Tomillero A; Moral M A Gateways to clinical trials. Methods and findings in experimental and clinical pharmacology (2008), 30(8), 643-72. Journal code: 7909595. ISSN:0379-0355. PubMed ID 19088949 AN 2009036942

42. Quintas-Cardama Alfonso; Verstovsek Srdan; Freireich Emil; Kantarjian Hagop; Chen Yi Wen; Zingaro Ralph Chemical and clinical development of darinaparsin, a novel organic arsenic derivative. Anti-cancer agents in medicinal chemistry (2008), 8(8), 904-9. Journal code: 101265649. E-ISSN:1875-5992. PubMed ID 19075572 AN 2009028174

43. Diaz Z; Mann K K; Marcoux S; Kourelis M; Colombo M; Komarnitsky P B; Miller W H Jr A novel arsenical has antitumor activity toward As2O3-resistant and MRP1/ABCC1-overexpressing cell lines. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K (2008), 22(10), 1853-63. Journal code: 8704895. E-ISSN:1476-5551. PubMed ID 18633430 AN 2008658565