Clinical activity of laromustine (Onrigin™) in hematologic malignancies

Expert Review of Hematology

Volumn 2, Issue 5, 2009, Pages 481-488

  Alvarado, Yesid ^a   Swords, Ronan ^a   Kelly, Kevin R ^a   Giles, Francis J ^b  

^a CTRC Institute for Drug Development   (United States)

^b University of Texas Health Science Center at San Antonio   (United States)

Author keywords

Alkylating agents; AML; ATG; Carbamoylation; Chloroethylation; Cloretazine; Laromustine; Leukemia; Onrigin ; SHP; Sulfonylhydrazine prodrug; VNP40101M

Indexed keywords

CLORETAZINE; CYTARABINE; ONRIGIN; UNCLASSIFIED DRUG;

ACUTE GRANULOCYTIC LEUKEMIA; ANTINEOPLASTIC ACTIVITY; BONE MARROW SUPPRESSION; CLINICAL TRIAL; GASTROINTESTINAL SYMPTOM; HEMATOLOGIC MALIGNANCY; HUMAN; IN VITRO STUDY; IN VIVO STUDY; INFECTION; LUNG DISEASE; MYELODYSPLASTIC SYNDROME; PRIORITY JOURNAL; REVIEW;

ANIMALS; ANTINEOPLASTIC AGENTS, ALKYLATING; CLINICAL TRIALS AS TOPIC; DRUG EVALUATION, PRECLINICAL; HEMATOLOGIC NEOPLASMS; HUMANS; HYDRAZINES; SULFONAMIDES;

EID: 77953393181     PISSN: 17474086     EISSN: None     Source Type: Journal    
DOI: 10.1586/ehm.09.38     Document Type: Review

References (63)

1. Hall AG, Tilby MJ. Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies. Blood Rev. 6(3), 163-173 (1992).
2. Chabner BA, Roberts TG Jr. Timeline: chemotherapy and the war on cancer. Nat. Rev. Cancer 5(1), 65-72 (2005).
3. Colvin M. Alkylating agents and platinum antitumor compounds. In: Cancer Medicine. Kufe D, Pollock R, Weichselbaum R et al. (Eds). BC Deacker, London, UK 759-779 (2003).
4. Montgomery JA, James R, McCaleb GS, Kirk MC, Johnston TP. Decomposition of N-(2-chloroethyl)-N-nitrosoureas in aqueous media. J. Med. Chem. 18(6), 568-571 (1975).
5. Montgomery JA, James R, McCaleb GS, Johnston TP. The modes of decomposition of 1,3-bis(2-chloroethyl)- 1-nitrosourea and related compounds. J. Med. Chem. 10(4), 668-674 (1967).
6. Weinkam RJ, Lin HS. Reactions of 1,3-bis(2-chloroethyl)-1-nitrosourea and 1-(2-chloroethyl)-3-cyclohexyl-1- nitrosourea in aqueous solution. J. Med. Chem. 22(10), 1193-1198 (1979).
7. Brundrett RB. Chemistry of nitrosoureas. Intermediacy of 4,5-dihydro-1,2,3- oxadiazole in 1,3-bis(2-chloroethyl)-1- nitrosourea decomposition. J. Med. Chem. 23(11), 1245-1247 (1980).
8. Kohn KW. Mechanistic approaches to new nitrosourea development. Recent Results Cancer Res. 76, 141-152 (1981).
9. Finch RA, Shyam K, Penketh PG, Sartorelli AC. 1,2-bis(methylsulfonyl)-1- (2-chloroethyl)-2-(methylamino) carbonylhydrazine (101M): a novel sulfonylhydrazine prodrug with broadspectrum antineoplastic activity. Cancer Res. 61(7), 3033-3038 (2001).
10. Penketh PG, Shyam K, Sartorelli AC. Comparison of DNA lesions produced by tumor-inhibitory 1,2-bis(sulfonyl) hydrazines and chloroethylnitrosoureas. Biochem. Pharmacol. 59(3), 283-291 (2000).
11. Briscoe WT, Duarte SP. Preferential alkylation by 1,3-bis(2-chloroethyl)- 1- nitrosourea (BCNU) of guanines with guanines as neighboring bases in DNA. Biochem. Pharmacol. 37(6), 1061-1066 (1988).
12. Pratviel G, Shyam K, Sartorelli AC. Cytotoxic and DNA-damaging effects of 1,2-bis(sulfonyl)hydrazines on human cells of the Mer+ and Mer- phenotype. Cancer Biochem. Biophys. 10(4), 365-375 (1989).
13. Ishiguro K, Shyam K, Penketh PG, Sartorelli AC. Role of O6-alkylguanine- DNA alkyltransferase in the cytotoxic activity of cloretazine. Mol. Cancer Ther. 4(11), 1755-1763 (2005).
14. Baumann RP, Shyam K, Penketh PG, Remack JS, Brent TP, Sartorelli AC. 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)- 2-[(methylamino)carbonyl]hydrazi ne (VNP40101M): II: role of O6- alkylguanine-DNA alkyltransferase in cytotoxicity. Cancer Chemother. Pharmacol. 53(4), 288-295 (2004).
15. Baumann RP, Seow HA, Shyam K, Penketh PG, Sartorelli AC. The antineoplastic efficacy of the prodrug cloretazine is produced by the synergistic interaction of carbamoylating and alkylating products of its activation. Oncol. Res. 15(6), 313-325 (2005).
16. Ishiguro K, Seow HA, Penketh PG, Shyam K, Sartorelli AC. Mode of action of the chloroethylating and carbamoylating moieties of the prodrug cloretazine. Mol. Cancer Ther. 5(4), 969-976 (2006).
17. Fernandez-Capetillo O, Lee A, Nussenzweig M, Nussenzweig A. H2AX: the histone guardian of the genome. DNA Repair (Amst.) 3(8-9), 959-967 (2004).
18. Bartkova J, Bakkenist CJ, Rajpert-De Meyts E et al. ATM activation in normal human tissues and testicular cancer. Cell Cycle 4(6), 838-845 (2005).
19. Penketh PG, Shyam K, Sartorelli AC. Mechanisms of resistance to alkylating agents. Cancer Treat. Res. 87, 65-81 (1996).
20. Meister A, Anderson ME. Glutathione. Annu. Rev. Biochem. 52, 711-760 (1983).
21. Rice KP, Penketh PG, Shyam K, Sartorelli AC. Differential inhibition of cellular glutathione reductase activity by isocyanates generated from the antitumor prodrugs cloretazine and BCNU. Biochem. Pharmacol. 69(10), 1463-1472 (2005).
22. Mao J, Xu Y, Wu D, Almassain B. Pharmacokinetics, mass balance, and tissue distribution of a novel DNA alkylating agent, VNP40101M, in rat. AAPS Pharm. Sci. 4(4), E24 (2002).
23. Murren J, Modiano M, Kummar S et al. A Phase I and pharmacokinetic study of VNP40101M, a new alkylating agent, in patients with advanced or metastatic cancer. Invest. New Drugs 23(2), 123-135 (2005).
24. Giles F, Thomas D, Garcia-Manero G et al. A Phase I and pharmacokinetic study of VNP40101M, a novel sulfonylhydrazine alkylating agent, in patients with refractory leukemia. Clin. Cancer Res. 10(9), 2908-2917 (2004).
25. Giles F, Verstovsek S, Thomas D et al. Phase I study of cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, combined with cytarabine in patients with refractory leukemia. Clin. Cancer Res. 11(21), 7817-7824 (2005).
26. Giles F, Rizzieri D, Karp J et al. Cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, in patients age 60 years or older with previously untreated acute myeloid leukemia. J. Clin. Oncol. 25(1), 25-31 (2007).
27. Bernstein I, Giles F, O'Brien S, Sullivan E, Vey N, Yang AS. Hypermethylation of O6-methylguanine-DNA methyltransferase (MGMT) predicts response to laromustine (cloretazine(R)) in patients with acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (MDS). ASH Annual Meeting Abstracts 112(11), 4463 (2008).
28. Mufti G, Rizzieri D, Vey N, Hudak D, Karp J, Giles F. Treatment with VNP40101M (cloretazine® ) in patients with high risk myelodysplastic syndromes (MDS): results of a subset population in a Phase II study. List of Abstracts from the 13th Congress of the EHA (2008).
29. Schiller GJ, DeAngelo DJ, Vey N et al. A Phase II study of VNP40101M in elderly patients (pts) with de novo poor risk acute myelogenous leukemia (AML). J. Clin. Oncol. (Suppl.) 26 (2008).
30. O'Brien S, Schiller G, Stuart RK, Hudak D, Giles F. Survival after complete response to treatment with laromustine (CLORETAZINE(® )) in elderly patients with de novo poor risk acute myelogenous leukemia (AML). ASH Annual Meeting Abstracts 112(11), 940 (2008).
31. Hills R, O'Brien S, Karsten V, Burnett AK, Giles F. A Retrospective comparison of matched elderly patients treated with laromustine (Cloretazine(® )) or best supportive care or low dose Ara-C in the LRF AML14 Trial. ASH Annual Meeting Abstracts 112(11), 2960 (2008).
32. Giles F, Verstovsek S, Faderl S et al. A Phase II study of cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, in patients with very high risk relapsed acute myeloid leukemia. Leuk. Res. 30(12), 1591-1595 (2006).
33. DeAngelo D, O'Brien SM, Vey N et al. A double blind placebo-controlled randomized Phase III study of high dose continuous infusion cytosine arabinoside (araC) with or without VNP40101M in patients (pts) with first relapse of acute myeloid leukemia (AML). J. Clin. Oncol. (26 Suppl.) (2008) (Abstract 7051).
34. Vey N, Pigneux A, Boscovic D et al. A double blind placebo-controlled randomized Phase III study of high dose continuous infusion cytosine arabinoside (ARAC) with or without VNP40101M (Cloretazine® ) in patients with first relapse of acute myeloid leukemia (AML). List of Abstracts from the 13th Congress of the EHA (2008).
35. Jemal A, Siegel R, Ward E et al. Cancer statistics, 2008. CA Cancer J. Clin. 58(2), 71-96 (2008).
36. Cheson BD, Bennett JM, Kopecky KJ et al. Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J. Clin. Oncol. 21(24), 4642-4649 (2003).
37. A systematic collaborative overview of randomized trials comparing idarubicin with daunorubicin (or other anthracyclines) as induction therapy for acute myeloid leukemia: AML collaborative group. Br. J. Haematol. 103(1), 100-109 (1998).
38. Estey EH, Thall PF, Cortes JE et al. Comparison of idarubicin + ara-C-, fludarabine + ara-C-, and topotecan + ara-C-based regimens in treatment of newly diagnosed acute myeloid leukemia, refractory anemia with excess blasts in transformation, or refractory anemia with excess blasts. Blood 98(13), 3575-3583 (2001).
39. Mayer RJ, Davis RB, Schiffer CA et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia: Cancer and Leukemia group B. N. Engl. J. Med. 331(14), 896-903 (1994).
40. Estey EH. Therapeutic options for acute myelogenous leukemia. Cancer 92(5), 1059-1073 (2001).
41. Burnett AK, Goldstone AH, Stevens RM et al. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukemia in first remission: results of MRC AML 10 trial: UK medical research council adult and children's leukemia working parties. Lancet 351(9104), 700-708 (1998).
42. Vey N, Bouabdallah R, Stoppa A et al. Autologous stem cell transplantation for acute myelogenous leukemia in first complete remission: a 6-year follow-up study of 101 patients from a single institution. Bone Marrow Transplant. 33(2), 177-182 (2004).
43. Blaise DP, Michel Boiron J, Faucher C et al. Reduced intensity conditioning prior to allogeneic stem cell transplantation for patients with acute myeloblastic leukemia as a first-line treatment. Cancer 104(9), 1931-1938 (2005). (Pubitemid 41513177)
44. Bloomfield CD, Lawrence D, Byrd JC et al. Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res. 58(18), 4173-4179 (1998).
45. Byrd JC, Mrozek K, Dodge RK et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461) Blood 100(13), 4325-4336 (2002).
46. Haferlach T, Schoch C, Loffler H et al. Morphologic dysplasia in de novo acute myeloid leukemia (AML) is related to unfavorable cytogenetics but has no independent prognostic relevance under the conditions of intensive induction therapy: results of a multiparameter analysis from the German AML Cooperative Group studies. J. Clin. Oncol. 21(2), 256-265 (2003).
47. Estey E. Acute myeloid leukemia and myelodysplastic syndromes in older patients. J. Clin. Oncol. 25(14), 1908-1915 (2007). (Pubitemid 46854425)
48. Greenberg P, Cox C, LeBeau MM et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89(6), 2079-2088 (1997).
49. Kantarjian H, Issa JP, Rosenfeld CS et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a Phase III randomized study. Cancer 106(8), 1794 - 1803 (2006).
50. Silverman LR, Demakos EP, Peterson BL et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J. Clin. Oncol. 20(10), 2429-2440 (2002).
51. Silverman LR, McKenzie DR, Peterson BL et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J. Clin. Oncol. 24(24), 3895-3903 (2006).
52. Oran B, Giralt S, Saliba R et al. Allogeneic hematopoietic stem cell transplantation for the treatment of high-risk acute myelogenous leukemia and myelodysplastic syndrome using reduced-intensity conditioning with fludarabine and melphalan. Biol. Blood Marrow Transplant. 13(4), 454-462 (2007). (Pubitemid 46421890)
53. Breems DA, Lowenberg B. Autologous stem cell transplantation in the treatment of adults with acute myeloid leukemia. Br. J. Haematol. 130(6), 825-833 (2005).
54. Gururangan S, Turner CD, Stewart CF et al. Phase I trial of VNP40101M (cloretazine) in children with recurrent brain tumors: a pediatric brain tumor consortium study. Clin. Cancer Res. 14(4), 1124-1130 (2008).
55. Badruddoja MA, Penne K, Desjardins A et al. Phase II study of cloretazine for the treatment of adults with recurrent glioblastoma multiforme. Neuro. Oncol. 9(1), 70-74 (2007).
56. Vey N, Coso D, Bardou VJ et al. The benefit of induction chemotherapy in patients age > or = 75 years. Cancer 101(2), 325-331 (2004).
57. Zheng LM, Li Z, Liu L, Song BL, King I. Anti-tumor efficacy of cloretazine (VNP40101M) alone and in combination with fludarabine in murine tumor and human xenograft tumor models. Cancer Chemother. Pharmacol. 60(1), 45-51 (2007).
58. Adams DJ, Sandvold ML, Myhren F, Jacobsen TF, Giles F, Rizzieri DA. Anti proliferative activity of ELACY (CP-4055) in combination with cloretazine (VNP40101M), idarubicin, gemcitabine, irinotecan and topotecan in human leukemia and lymphoma cells. Leuk. Lymphoma 49(4), 786-797 (2008).
59. D'Atri S, Piccioni D, Castellano A et al. Chemosensitivity to triazene compounds and O6-alkylguanine-DNA alkyltransferase levels: studies with blasts of leukaemic patients. Ann. Oncol. 6(4), 389-393 (1995).
60. Gerson SL. Clinical relevance of MGMT in the treatment of cancer. J. Clin. Oncol. 20(9), 2388-2399 (2002).
61. Brandwein JM, Yang L, Schimmer AD et al. A Phase II study of temozolomide therapy for poor-risk patients aged ?60 years with acute myeloid leukemia: low levels of MGMT predict for response. Leukemia 21(4), 821-824 (2007).
62. Spiro TP, Liu L, Majka S, Haaga J, Willson JK, Gerson SL. Temozolomide: the effect of once- and twice-a-day dosing on tumor tissue levels of the DNA repair protein O(6)-alkylguanine-DNAalkyltransferase. Clin. Cancer Res. 7(8), 2309-2317 (2001).
63. Seiter K, Liu D, Loughran T, Siddiqui A, Baskind P, Ahmed T. Phase I study of temozolomide in relapsed/refractory acute leukemia. J. Clin. Oncol. 20(15), 3249-3253 (2002).