Genomes and Genes
nitrogen mustard compounds
Summary: A group of alkylating agents derived from mustard gas, with the sulfur replaced by nitrogen. They were formerly used as toxicants and vesicants, but now function as antineoplastic agents. These compounds are also powerful mutagens, teratogens, immunosuppressants, and carcinogens.
- Teichert J, Sohr R, Baumann F, Hennig L, Merkle K, Caca K, et al. Synthesis and characterization of some new phase II metabolites of the alkylator bendamustine and their identification in human bile, urine, and plasma from patients with cholangiocarcinoma. Drug Metab Dispos. 2005;33:984-92 pubmed..Results indicate the importance of phase II conjugation in the elimination of bendamustine, besides phase I metabolism and hydrolytic degradation, and require further investigation. ..
- Guise C, Abbattista M, Singleton R, Holford S, Connolly J, Dachs G, et al. The bioreductive prodrug PR-104A is activated under aerobic conditions by human aldo-keto reductase 1C3. Cancer Res. 2010;70:1573-84 pubmed publisher..A survey of normal tissue AKR1C3 expression suggests the potential for tumor-selective PR-104A activation by this mechanism. These findings have significant implications for the clinical development of PR-104. ..
- Ohmachi K, Niitsu N, Uchida T, Kim S, Ando K, Takahashi N, et al. Multicenter phase II study of bendamustine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2013;31:2103-9 pubmed publisher..The present phase II study assessed the efficacy and safety of bendamustine plus rituximab (BR) in this population...
- Balfour J, Goa K. Bendamustine. Drugs. 2001;61:631-8; discussion 639-40 pubmed..The most common adverse events in patients receiving bendamustine are haematological events and gastrointestinal disturbances. Bendamustine has a relatively low propensity to induce alopecia. ..
- Gu Y, Patterson A, Atwell G, Chernikova S, Brown J, Thompson L, et al. Roles of DNA repair and reductase activity in the cytotoxicity of the hypoxia-activated dinitrobenzamide mustard PR-104A. Mol Cancer Ther. 2009;8:1714-23 pubmed publisher..This study shows that hypoxia, reductase activity, and DNA interstrand cross-link repair proficiency are key variables that interact to determine PR-104A sensitivity. ..
- Gu Y, Atwell G, Wilson W. Metabolism and excretion of the novel bioreductive prodrug PR-104 in mice, rats, dogs, and humans. Drug Metab Dispos. 2010;38:498-508 pubmed publisher..Based on these metabolite profiles, biotransformation of PR-104 in rodents is markedly different from that in humans, suggesting that rodents may not be appropriate for modeling human biotransformation and toxicology of PR-104. ..
- Cheson B, Wendtner C, Pieper A, Dreyling M, Friedberg J, Hoelzer D, et al. Optimal use of bendamustine in chronic lymphocytic leukemia, non-Hodgkin lymphomas, and multiple myeloma: treatment recommendations from an international consensus panel. Clin Lymphoma Myeloma Leuk. 2010;10:21-7 pubmed publisher..This report, representing the conclusions of that meeting, should provide guidance for the clinician until definitive dose-finding studies have been conducted. ..
- Ohmachi K, Ando K, Ogura M, Uchida T, Itoh K, Kubota N, et al. Multicenter phase II study of bendamustine for relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma. Cancer Sci. 2010;101:2059-64 pubmed publisher..Common non-hematologic toxicities included mild gastrointestinal events and fatigue. These results demonstrate the high efficacy and tolerability of single-agent bendamustine in relapsed patients with indolent B-NHL or MCL histologies. ..
- Guise C, Abbattista M, Tipparaju S, Lambie N, Su J, Li D, et al. Diflavin oxidoreductases activate the bioreductive prodrug PR-104A under hypoxia. Mol Pharmacol. 2012;81:31-40 pubmed publisher..Immunostaining for carbonic anhydrase 9 (CAIX), reportedly an endogenous marker of hypoxia, revealed only moderate coexpression (9.6%) of both CAIX and POR across a subset of five cancer types. ..
- Rigacci L, Puccini B, Cortelazzo S, Gaidano G, Piccin A, D Arco A, et al. Bendamustine with or without rituximab for the treatment of heavily pretreated non-Hodgkin's lymphoma patients : A multicenter retrospective study on behalf of the Italian Lymphoma Foundation (FIL). Ann Hematol. 2012;91:1013-22 pubmed publisher..In summary, this retrospective study shows that treatment with bendamustine alone or in combination with rituximab is a safe and effective regimen in a subset of multi-resistant patients. ..
- Horn J, Kleber M, Hieke S, Schmitt Gräff A, Wasch R, Engelhardt M. Treatment option of bendamustine in combination with rituximab in elderly and frail patients with aggressive B-non-Hodgkin lymphoma: rational, efficacy, and tolerance. Ann Hematol. 2012;91:1579-86 pubmed publisher..6--n.r.), respectively. We conclude that R-B is a feasible and safe therapy option in a-B-NHL patients not qualifying for R-CHOP but needs to be further assessed in larger subsequent trials, these currently being under way. ..
- Su T, Lin Y, Chou T, Zhang X, Bacherikov V, Chen C, et al. Potent antitumor 9-anilinoacridines and acridines bearing an alkylating N-mustard residue on the acridine chromophore: synthesis and biological activity. J Med Chem. 2006;49:3710-8 pubmed..Of these agents, compounds 27a and 27c were shown to have potent antitumor activity in nude mice bearing the human breast carcinoma MX-1 xenograft. The therapeutic efficacies of these two agents are comparable to that of taxol. ..
- Schmittel A, Knödler M, Hortig P, Schulze K, Thiel E, Keilholz U. Phase II trial of second-line bendamustine chemotherapy in relapsed small cell lung cancer patients. Lung Cancer. 2007;55:109-13 pubmed..Therefore, single-agent bendamustine is a treatment option for patients with SCLC, who have responded to initial platinum containing chemotherapy and should further be investigated in randomized trials. ..
- Rasschaert M, Schrijvers D, Van den Brande J, Dyck J, Bosmans J, Merkle K, et al. A phase I study of bendamustine hydrochloride administered day 1+2 every 3 weeks in patients with solid tumours. Br J Cancer. 2007;96:1692-8 pubmed..3% (range 2.7-26%). The MTD of BM in the present dose schedule was 180 mg m(-2) on day 1+2. Thrombocytopaenia was dose limiting. The recommended dose for future phase II trials with this schedule is 160 mg m(-2) per day. ..
- Chow K, Boehrer S, Geduldig K, Krapohl A, Hoelzer D, Mitrou P, et al. In vitro induction of apoptosis of neoplastic cells in low-grade non-Hodgkin's lymphomas using combinations of established cytotoxic drugs with bendamustine. Haematologica. 2001;86:485-93 pubmed
- Zulkowski K, Kath R, Semrau R, Merkle K, Hoffken K. Regression of brain metastases from breast carcinoma after chemotherapy with bendamustine. J Cancer Res Clin Oncol. 2002;128:111-3 pubmed..Thus, it may be considered as another therapeutic strategy against metastatic brain cancer. However, this finding warrants further investigation in clinical trials. ..
- Gaul L, Mandl Weber S, Baumann P, Emmerich B, Schmidmaier R. Bendamustine induces G2 cell cycle arrest and apoptosis in myeloma cells: the role of ATM-Chk2-Cdc25A and ATM-p53-p21-pathways. J Cancer Res Clin Oncol. 2008;134:245-53 pubmed..Bendamustine induces ATM-Chk2-Cdc2-mediated G2 arrest and p53 mediated apoptosis. Inhibition of p38 MAPK augments apoptosis and abrogates G2 arrest and can be considered as a new therapeutic strategy in combination with bendamustine. ..
- Knauf W, Lissichkov T, Aldaoud A, Liberati A, Loscertales J, Herbrecht R, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27:4378-84 pubmed publisher..Bendamustine offers significantly greater efficacy than chlorambucil, and a manageable toxicity profile, when used as first-line therapy in patients with advanced CLL. ..
- Chow K, Nowak D, Boehrer S, Ruthardt M, Knau A, Hoelzer D, et al. Synergistic effects of chemotherapeutic drugs in lymphoma cells are associated with down-regulation of inhibitor of apoptosis proteins (IAPs), prostate-apoptosis-response-gene 4 (Par-4), death-associated protein (Daxx) and with enforced caspase activ. Biochem Pharmacol. 2003;66:711-24 pubmed..The above described mechanisms were already assessable at a point where the effects of synergistic or antagonistic combinations could not yet be discriminated quantitatively by the level of apoptosis rate of the lymphoma cells. ..
- Schrijvers D, Vermorken J. Phase I studies with bendamustine: an update. Semin Oncol. 2002;29:15-8 pubmed..This article presents an overview of the recent phase I trials and a summary of ongoing clinical trials. ..
- Gandhi V. Metabolism and mechanisms of action of bendamustine: rationales for combination therapies. Semin Oncol. 2002;29:4-11 pubmed..The rationales behind bendamustine combination regimens and the importance of the sequence of administration of different drugs are explored. ..
- Forero Torres A, Saleh M. Bendamustine in non-Hodgkin lymphoma: the double-agent that came from the Cold War. Clin Lymphoma Myeloma. 2007;8 Suppl 1:S13-7 pubmed..This article provides a review of studies using bendamustine in the treatment of non-Hodgkin lymphomas. ..
- Ujjani C, Cheson B. Efficacy of bendamustine in rituximab-refractory indolent B-cell non-Hodgkin lymphoma: review of a pivotal trial. Future Oncol. 2011;7:9-14 pubmed publisher..3 months, as well as easy tolerability. The most common toxicities were nausea, myelosuppression and infection. These results confirm bendamustine's role in rituximab-refractory indolent B-cell NHL. ..
- Lee C, Chou T, Su T, Yu J, Shao L, Yu A. BO-0742, a derivative of AHMA and N-mustard, has selective toxicity to drug sensitive and drug resistant leukemia cells and solid tumors. Cancer Lett. 2009;276:204-11 pubmed publisher..Thus, BO-0742 is a potent anti-cancer agent worthy of further clinical development. ..
- Weidmann E, Kim S, Rost A, Schuppert H, Seipelt G, Hoelzer D, et al. Bendamustine is effective in relapsed or refractory aggressive non-Hodgkin's lymphoma. Ann Oncol. 2002;13:1285-9 pubmed..Bendamustine as a single agent is effective against aggressive lymphoma, even in cases of refractory disease. Further studies are warranted to determine the significance of bendamustine in the treatment of aggressive lymphomas. ..
- Konstantinov S, Kostovski A, Topashka Ancheva M, Genova M, Berger M. Cytotoxic efficacy of bendamustine in human leukemia and breast cancer cell lines. J Cancer Res Clin Oncol. 2002;128:271-8 pubmed..The specific spectrum of activity and the unexpectedly low clastogenicity support the hypothesis that bendamustine in not a typical alkylating agent but exerts an additional mode of action, possibly as a purine antimetabolite. ..
- Panasci L, Xu Z, Bello V, Aloyz R. The role of DNA repair in nitrogen mustard drug resistance. Anticancer Drugs. 2002;13:211-20 pubmed..Studies on human epithelial tumor cell lines suggest that HRR rather than NHEJ plays a role in nitrogen mustard sensitivity. ..
- Friedberg J, Vose J, Kelly J, Young F, Bernstein S, Peterson D, et al. The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood. 2011;117:2807-12 pubmed publisher..On the basis of these promising results, the US cooperative groups have initiated randomized trials to evaluate this regimen in follicular and mantle cell lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT00547534. ..
- Leoni L, Hartley J. Mechanism of action: the unique pattern of bendamustine-induced cytotoxicity. Semin Hematol. 2011;48 Suppl 1:S12-23 pubmed publisher..This review will discuss the current understanding and hypotheses regarding bendamustine mechanisms of action and suggest future investigations that would shed light on the many unanswered questions. ..
- Ogura M, Ando K, Taniwaki M, Watanabe T, Uchida T, Ohmachi K, et al. Feasibility and pharmacokinetic study of bendamustine hydrochloride in combination with rituximab in relapsed or refractory aggressive B cell non-Hodgkin's lymphoma. Cancer Sci. 2011;102:1687-92 pubmed publisher..In conclusion, bendamustine 120 mg/m(2) plus rituximab 375 mg/m(2) was feasible and generally well tolerated, with promising efficacy in relapsed or refractory aggressive B-NHL. ..
- Fowler N, Kahl B, Lee P, Matous J, Cashen A, Jacobs S, et al. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II VERTICAL study. J Clin Oncol. 2011;29:3389-95 pubmed publisher..Transient grade 3 to 4 neuropathy occurred in 11% of patients. The combination of bortezomib, bendamustine, and rituximab is highly active in patients with follicular lymphoma who have received previous treatment. ..
- Visani G, Malerba L, Stefani P, Capria S, Galieni P, Gaudio F, et al. BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients. Blood. 2011;118:3419-25 pubmed publisher..In conclusion, the new BeEAM regimen is safe and effective for heavily pretreated lymphoma patients. The study was registered at European Medicines Agency (EudraCT number 2008-002736-15). ..
- Heider A, Niederle N. Efficacy and toxicity of bendamustine in patients with relapsed low-grade non-Hodgkin's lymphomas. Anticancer Drugs. 2001;12:725-9 pubmed..Bendamustine proved to be very effective and was well tolerated in pretreated patients with relapsed or primary resistant low-grade NHL. ..
- Jameson M, Rischin D, Pegram M, Gutheil J, Patterson A, Denny W, et al. A phase I trial of PR-104, a nitrogen mustard prodrug activated by both hypoxia and aldo-keto reductase 1C3, in patients with solid tumors. Cancer Chemother Pharmacol. 2010;65:791-801 pubmed publisher..The recommended dose of PR-104 as a single agent for phase II trials is 1,100 mg/m(2) and further trials are underway. ..
- Cheson B, Rummel M. Bendamustine: rebirth of an old drug. J Clin Oncol. 2009;27:1492-501 pubmed publisher..However, the availability of bendamustine provides another effective treatment option for patients with lymphoid malignancies. ..
- Lissitchkov T, Arnaudov G, Peytchev D, Merkle K. Phase-I/II study to evaluate dose limiting toxicity, maximum tolerated dose, and tolerability of bendamustine HCl in pre-treated patients with B-chronic lymphocytic leukaemia (Binet stages B and C) requiring therapy. J Cancer Res Clin Oncol. 2006;132:99-104 pubmed
- Pönisch W, Rozanski M, Goldschmidt H, Hoffmann F, Boldt T, Schwarzer A, et al. Combined bendamustine, prednisolone and thalidomide for refractory or relapsed multiple myeloma after autologous stem-cell transplantation or conventional chemotherapy: results of a Phase I clinical trial. Br J Haematol. 2008;143:191-200 pubmed publisher..We conclude that BPT therapy was well tolerated in patients with relapsed or refractory MM, with a response rate higher than 80%. The maximum tolerated dose of thalidomide was not reached in this study. ..
- Guise C, Wang A, Theil A, Bridewell D, Wilson W, Patterson A. Identification of human reductases that activate the dinitrobenzamide mustard prodrug PR-104A: a role for NADPH:cytochrome P450 oxidoreductase under hypoxia. Biochem Pharmacol. 2007;74:810-20 pubmed..We conclude that CYPOR is an important PR-104A reductase, but that other flavoenzymes also contribute to its activation in hypoxic SiHa cells. ..
- Eichbaum M, Schuetz F, Khbeis T, Lauschner I, Foerster F, Sohn C, et al. Weekly administration of bendamustine as salvage therapy in metastatic breast cancer: final results of a phase II study. Anticancer Drugs. 2007;18:963-8 pubmed..Future trials should evaluate higher single doses of bendamustine in a weekly schedule. ..
- Marchini S, Ciro M, Gallinari F, Geroni C, Cozzi P, D INCALCI M, et al. Alpha-bromoacryloyl derivative of distamycin A (PNU 151807): a new non-covalent minor groove DNA binder with antineoplastic activity. Br J Cancer. 1999;80:991-7 pubmed
- Aivado M, Schulte K, Henze L, Burger J, Finke J, Haas R. Bendamustine in the treatment of chronic lymphocytic leukemia: results and future perspectives. Semin Oncol. 2002;29:19-22 pubmed..Complete hematologic remission was achieved in six of 21 patients and a further eight patients achieved a partial hematologic remission. The main toxicities were hematologic; nonhematologic side effects were mild and uncommon. ..
- Dubbelman A, Jansen R, Rosing H, Darwish M, Hellriegel E, Robertson P, et al. Metabolite profiling of bendamustine in urine of cancer patients after administration of [14C]bendamustine. Drug Metab Dispos. 2012;40:1297-307 pubmed publisher..The range of metabolic reactions is generally consistent with those reported for rat urine and bile, suggesting that the overall processes involved in metabolic elimination are qualitatively the same in rats and humans...
- Bergmann M, Goebeler M, Herold M, Emmerich B, Wilhelm M, Ruelfs C, et al. Efficacy of bendamustine in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase I/II study of the German CLL Study Group. Haematologica. 2005;90:1357-64 pubmed..Based on these results, the recommended optimal therapeutic dose of bendamustine in refractory CLL is 70 mg/m2 on days 1 and 2 every 4 weeks. ..
- Weide R, Hess G, Koppler H, Heymanns J, Thomalla J, Aldaoud A, et al. High anti-lymphoma activity of bendamustine/mitoxantrone/rituximab in rituximab pretreated relapsed or refractory indolent lymphomas and mantle cell lymphomas. A multicenter phase II study of the German Low Grade Lymphoma Study Group (GLSG). Leuk Lymphoma. 2007;48:1299-306 pubmed..BMR is a very effective new outpatient immuno-chemotherapy with low toxicity for patients with relapsed/refractory FL, MCL and other indolent lymphomas...
- von Minckwitz G, Chernozemsky I, Sirakova L, Chilingirov P, Souchon R, Marschner N, et al. Bendamustine prolongs progression-free survival in metastatic breast cancer (MBC): a phase III prospective, randomized, multicenter trial of bendamustine hydrochloride, methotrexate and 5-fluorouracil (BMF) versus cyclophosphamide, methotrexate and 5. Anticancer Drugs. 2005;16:871-7 pubmed..BMF caused more mucositis and leukopenias. Thus, bendamustine, when replacing cyclophosphamide in the CMF combination, can be expected to produce longer progression-free survival in first-line treatment of MBC. ..
- Fenk R, Michael M, Zohren F, Graef T, Czibere A, Bruns I, et al. Escalation therapy with bortezomib, dexamethasone and bendamustine for patients with relapsed or refractory multiple myeloma. Leuk Lymphoma. 2007;48:2345-51 pubmed..In conclusion, this treatment algorithm resulted in responses in the majority of heavily pre-treated patients while at the same time restricting the toxicity of triple combination therapy to only 14% of non-responding patients. ..
- Friedberg J, Cohen P, Chen L, Robinson K, Forero Torres A, La Casce A, et al. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol. 2008;26:204-10 pubmed publisher..These findings are promising and will serve as a benchmark for future clinical trials in this novel patient population. ..
- Robinson K, Williams M, van der Jagt R, Cohen P, Herst J, Tulpule A, et al. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin's lymphoma. J Clin Oncol. 2008;26:4473-9 pubmed publisher..Bendamustine plus rituximab is an active combination in patients with relapsed indolent and mantle cell lymphoma. ..
- Roué G, Lopez Guerra M, Milpied P, Perez Galan P, Villamor N, Montserrat E, et al. Bendamustine is effective in p53-deficient B-cell neoplasms and requires oxidative stress and caspase-independent signaling. Clin Cancer Res. 2008;14:6907-15 pubmed publisher..Our findings support the use of bendamustine as a therapeutic agent, alone or in combination, for CLL and MCL with p53 alterations and describe the molecular basis of its activity in these entities. ..
- Gu Y, Guise C, Patel K, Abbattista M, Li J, Lie J, et al. Reductive metabolism of the dinitrobenzamide mustard anticancer prodrug PR-104 in mice. Cancer Chemother Pharmacol. 2011;67:543-55 pubmed publisher..PR-104 is extensively reduced in mouse tissues, apparently via oxygen-independent two-electron reduction, with a tissue distribution that broadly reflects toxicity. ..
- Rummel M, Al Batran S, Kim S, Welslau M, Hecker R, Kofahl Krause D, et al. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. J Clin Oncol. 2005;23:3383-9 pubmed..Thrombocytopenia was rare, with only 3% grade 3 and 4. These results demonstrate that the BR combination is a highly active regimen in the treatment of low-grade lymphomas and mantle cell lymphomas. ..