Disease relevance of SDX-105

• Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma [1].
• Bendamustine is a novel cytostatic agent, with activity in non-Hodgkin's lymphomas including B-chronic lymphocytic leukemia (B-CLL) [2].
• In vitro evaluation of bendamustine induced apoptosis in B-chronic lymphocytic leukemia [2].
• Bendamustine has a relatively low propensity to induce alopecia [3].
• Bendamustine as monotherapy or as part of combination chemotherapy protocols for first-line or subsequent treatment produced objective response rates of 61 to 97% in patients with Hodgkin's disease or non-Hodgkin's lymphoma (NHL) [41 to 48% in high grade NHL] [3].

High impact information on SDX-105

• In conclusion, this study demonstrates for the first time the in vitro efficacy of bendamustine in inducing apoptosis in B-CLL cells alone and in combination with fludarabine [2].
• Here, we investigated the in vitro ability of bendamustine to induce apoptosis on freshly isolated peripheral lymphocytes in B-CLL and analyze the potential underlying mechanisms of action for inducing apoptosis [2].
• In CLL cells taken from 37 previously treated and untreated CLL patients, we investigated the influence of bendamustine alone, and in combination with fludarabine, on the induction of apoptosis and changes of Bcl-2 and Bax expression on mRNA and protein level using the RNase protection assay or flow cytometry, respectively [2].
• Bendamustine was originally synthesized with the intention of producing an antineoplastic agent with low toxicity and both alkylating and antimetabolic properties [4].
• Bendamustine in the treatment of chronic lymphocytic leukemia: results and future perspectives [5].

Chemical compound and disease context of SDX-105

• Preliminary clinical studies with bendamustine, an alkylating agent with a purine nucleus, provide strong evidence that this drug is a highly effective cytostatic in low grade lymphomas [6].
• Nucleoside analogs in development for non-Hodgkin's lymphoma (NHL) include clofarabine, troxacitabine, and bendamustine, a hybrid of an alkylating nitrogen mustard group and a purine-like benzimidazole, with demonstrated activity in NHL [7].
• CONCLUSIONS: Bendamustine can efficaciously and safely replace cyclophosphamide, as used in standard COP therapy, for the treatment of patients with indolent NHL and mantle cell lymphoma [8].
• PURPOSE: Bendamustine hydrochloride, an anti-neoplastic agent with unique mechanism of action, is known to cause impressive remissions in relapsed non-Hodgkin's lymphoma and chronic lymphocytic leukaemia (CLL) [9].
• METHODS: A total of 164 patients with follicular lymphoma (grade 1/2), mantle cell lymphoma or lymphoplasmacytic lymphoma (immunocytoma) was randomised to treatment with vincristine 2 mg (day 1) and prednisone 100 mg/m2 (days 1-5) + bendamustine 60 mg/m2 (days 1-5) or + cyclophosphamide 400 mg/m2 (days 1-5) for a total of eight 21-day cycles [8].

Biological context of SDX-105

• CONCLUSIONS: The maximum tolerated dose of weekly bendamustine given as a 30-min i.v. infusion is 80 mg/m2, mouth dryness, fatigue and fever are dose-limiting [10].
• Measuring CD4(+) lymphocyte counts may be helpful in determining the risk of PCP in patients treated with bendamustine [11].
• In multiple pretreated or otherwise severely immunocompromised patients bendamustine might lead to additional immunosuppression with subsequent infectious complications [12].
• Fludarabine and bendamustine in refractory and relapsed indolent lymphoma--a multicenter phase I/II Trial of the east german society of hematology and oncology (OSHO) [13].
• The results of both WBAR and quantitative tissue distribution studies suggest that bendamustine was selectively taken up from the blood by liver and kidney tissues [14].

Anatomical context of SDX-105

• Bendamustine reduces the number of circulating B lymphocytes by over 90% and shows only partial cross-resistance with other alkylating agents, making it an ideal candidate for the treatment of CLL and for use in combination with other alkylating agents [5].
• The antagonism of the combination of bendamustine and anthracyclines appeared to be due to inhibition of depolarization of mitochondrial-membrane potential and caspase-3-activity during apoptosis of the studied cell lines [6].
• As a measure of hematological toxicity, the formation of chromosomal aberrations was investigated in bone marrow cells isolated from mice treated with low non-toxic doses of bendamustine and lomustine [15].
• Characterization of two phase I metabolites of bendamustine in human liver microsomes and in cancer patients treated with bendamustine hydrochloride [16].

Associations of SDX-105 with other chemical compounds

• It was first synthesized in 1963 in the German Democratic Republic. Bendamustine is chemically related to the alkylating agent chlorambucil, with the benzene ring in the chlorambucil molecule replaced by a 1-methyl-benzimidazole moiety [4].
• The combination of bendamustine/vincristine/prednisolone (BOP) has been compared with cyclophosphamide/vincristine/prednisolone (COP) in a phase III study involving 162 patients with low-grade NHL [17].
• Because polar biliary conjugates were expected metabolites of bendamustine, three cysteine S-conjugates were synthesized, purified by quantitative high-performance liquid chromatography (HPLC), and characterized by NMR spectroscopy and mass spectrometry (MS) [18].
• Thus, bendamustine, when replacing cyclophosphamide in the CMF combination, can be expected to produce longer progression-free survival in first-line treatment of MBC [19].
• We conclude that bendamustine has little or no clinically relevant activity in patients with cisplatin-refractory GCT or relapsed disease after high-dose chemotherapy [20].

Gene context of SDX-105

• A general feature was the decline of the CD4/CD8 ratio: mean before therapy: 1.36; after two courses: 0.98; after four courses: 0.6, as documented in all patients who received at least two courses of bendamustine (n = 12) [12].
• CONCLUSION: This trial demonstrates efficacy of bendamustine in relapsed SCLC and a favourable toxicity profile [21].
• PURPOSE: The purpose of this study was to compare the efficacy and toxicity of bendamustine, vincristine + prednisone (BOP) with a standard regimen of cyclophosphamide, vincristine + prednisone (COP) in patients with previously untreated advanced indolent non-Hodgkin's lymphoma (NHL) and mantle cell lymphoma [8].
• We have developed a new chemoimmunotherapy for patients with relapsed or refractory CD20-positive indolent lymphomas and CLL by combining the chemotherapeutic agents Bendamustine (B) and Mitoxantrone (M) with the monoclonal antibody Rituximab [22].
• Two i.v. regimens, bendamustine, methotrexate and 5-fluorouracil (BMF) and cyclophosphamide, methotrexate and 5-fluorouracil (CMF) were compared as first-line therapy in a randomized, open, multicenter phase III trial including 364 patients with metastatic breast cancer (MBC) [19].

Analytical, diagnostic and therapeutic context of SDX-105

• Although bendamustine has been in clinical use for over three decades, the early clinical trials do not conform to present-day standards of good clinical practice [23].
• Three of the complete responders had no chemotherapy prior to bendamustine [12].
• Determination of a cytostatic agent, bendamustine, in plasma using capillary gas chromatography with nitrogen-selective detection [24].
• It can be concluded that bendamustine in the dose and application schedule used here is active in the salvage therapy of women with advanced breast cancer [25].
• It was the aim of this study to investigate whether leukemia P388 being an important murine transplantation tumor may alter the plasma concentration-time profiles of the alkylating antineoplastic agent bendamustine (1) in mice [26].

References