Disease relevance of Treosulphan

• The risk of leukemic complications in this subgroup was compared with the risk in 312 patients treated with other alkylating agents for Hodgkin's disease, and with the risk in 553 patients treated with dihydroxybusulfan for ovarian carcinoma [1].
• By coculturing multiple myeloma cells with bone marrow stromal cells (BMSCs), we observed a CAM-DR of about 50% to melphalan, treosulfan, doxorubicin, dexamethasone, and bortezomib, which was not reversed by secreted soluble factors [2].
• In consideration of antineoplastic activity and limited organ toxicity, inclusion of high-dose treosulfan in combination protocols with autologous peripheral blood stem cell transplantation seems worthwhile [3].
• OBJECTIVE: Treosulfan is a prodrug with a specific clinical activity in ovarian carcinoma and other solid tumors [4].
• Phase I trial combining gemcitabine and treosulfan in advanced cutaneous and uveal melanoma patients [5].

Psychiatry related information on Treosulphan

• Assuming that imatinib could be included in pretransplantation conditioning therapies, we tested whether combinations of imatinib and gamma-irradiation or alkylating agents such as busulfan or treosulfan would display synergistic activity in BCR-ABL-positive chronic myelogenous leukaemia BV173 and EM-3 cell lines [6].

High impact information on Treosulphan

• To this end, C57BL/6J (B6) mice were treated with soluble formulations of either busulfan (Busulfex) or the closely related compound treosulfan, followed by transplantation of bone marrow cells from EGFP-transgenic (B6-EGFP.Tg) donor mice [7].
• The maximum tolerated dose of high-dose treosulfan is 47 g/m2 [3].
• METHODS: Three groups of BALB/c mice were treated with treosulfan, cyclophosphamide, or busulfan at sublethal doses that maintained survival without bone marrow support [4].
• Following combination chemotherapy, treosulfan-induced DNA crosslinks persisted, still being detectable 48 h post-treatment, supporting the hypothesis that gemcitabine potentiates treosulfan-induced cytotoxicity [5].
• CONCLUSION: Our data provide evidence for a strong antileukemic effect of treosulfan in both cell lines and AML blasts from patients at concentrations below the plasma levels described at standard dose levels [8].

Chemical compound and disease context of Treosulphan

• We conducted a phase I trial in advanced melanoma patients to determine the optimal dose of gemcitabine to be combined with treosulfan [5].
• Here, in vivo antileukaemic activity of treosulfan is compared with the activity of equitoxic doses of cyclophosphamide or busulfan for the first time using human acute lymphoblastic leukaemia (ALL)-models of paediatric origin xenotransplanted into non-obese diabetic (NOD)/severe combined immunodeficient (SCID) mice [9].
• Combination chemotherapy for choroidal melanoma: ex vivo sensitivity to treosulfan with gemcitabine or cytosine arabinoside [10].
• In all three carcinomas, treosulfan caused more pronounced growth reduction than did equitoxic doses of the alkylator cyclophosphamide [11].
• We did a retrospective, multicenter analysis to assess the feasibility of conditioning with fludarabine and treosulfan before allogeneic SCT in multiple myeloma patients [12].

Biological context of Treosulphan

• Furthermore, long-term preincubation with bryostatin-1 or TPA, both of which are known to down-regulate PKC protein levels, likewise inhibited treosulfan-induced apoptosis [8].
• DNA alkylation and interstrand cross-linking by treosulfan [13].
• Bcl-2 provided only moderate protection from synergistic induction of glioma cell death by treosulfan and BSO [14].
• In the present study, we report that permanent donor-specific tolerance and stable mixed multilineage chimerism can successfully be achieved across haploidentical MHC barriers when Treosulfan is administered in combination with anti-T-cell mAb and T-cell-depleted donor bone marrow cells [15].
• Clinical pharmacokinetics of intravenous treosulfan in patients with advanced solid tumors [16].

Anatomical context of Treosulphan

• Treatment with treosulfan resulted in reduced mRNA expression of IL-12 and interferon (IFN)-gamma in draining lymph nodes and reduced numbers of IFN-gamma-secreting MOG-specific T cells [17].
• In treosulfan-treated K562 cells, cross-links form slowly, reaching a peak at approximately 24 h [13].
• Treosulfan was applied to different subsets of cultured human blood mononuclear cells in order to asses the effects on human immune cells in vitro: Treosulfan reduced proliferative capacity and increased apoptosis in T cells and antigen-presenting cells [17].
• Action of treosulfan in myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis and human lymphocytes [17].
• Treosulphan has recently demonstrated antileukaemic activity and potent haematopoietic stem cell toxicity [18].

Associations of Treosulphan with other chemical compounds

• We investigated a dose-reduced conditioning regimen consisting of treosulfan and fludarabine followed by allogeneic stem cell transplantation (SCT) in 26 patients with secondary AML or MDS [19].
• Patients received combined daily treosulfan chemotherapy (500 mg) with rofecoxib (25 mg) [20].
• Comparison of single-, double- or triple-exposure protocols for the rodent bone marrow/peripheral blood micronucleus assay using 4-aminobiphenyl and treosulphan [21].
• The treatment that immediately preceded oral treosulfan was standard-dose platin-based chemotherapy [22].

Gene context of Treosulphan

• Metronomic oral low-dose treosulfan chemotherapy combined with cyclooxygenase-2 inhibitor in pretreated advanced melanoma: a pilot study [20].
• Simultaneous inhibition of COX-2 significantly increased the extent to which treosulfan suppressed cell proliferation, without inducing cytotoxicity [20].
• CD95/CD95 ligand-independent potentiation of treosulfan cytotoxicity by BSO in malignant glioma cells in vitro and in vivo [23].
• In light of the beneficial effects in EAE in vivo and the in vitro immunosuppressive and pro-apoptotic capacities in cultured human mononuclear immune effector cells, these data may support a potential role of treosulfan, an agent with high immunosuppressive capacity and low toxicity, in the treatment of MS [17].
• We report three patients with relapsed ovarian cancer who developed femoral head necrosis requiring endoprosthetic hip surgery 16-35 months after high-dose chemotherapy (HDC) with treosulfan (47 and 56 g/m(2) body-surface area (BSA)) given as 3-25 h infusions and followed by autologous peripheral blood stem cell (PBSC) transplantation [24].

Analytical, diagnostic and therapeutic context of Treosulphan

• Clinical phase I dose escalation and pharmacokinetic study of high-dose chemotherapy with treosulfan and autologous peripheral blood stem cell transplantation in patients with advanced malignancies [3].
• The FM 2 breast carcinoma, finally, was the only xenograft whose growth was not influenced by treosulfan at doses up to that which was lethal to 50% of the treated mice (LD50 value) [11].
• METHODS: A sensitive method for the determination of treosulfan in plasma and urine by reversed-phase high-performance liquid chromatography had previously been developed [25].
• Our results suggest that treosulfan might be an appropriate candidate for novel treatment protocols for patients with multiple myeloma [26].
• Because of this activity as well as the known low toxicity and good clinical compatibility of treosulfan, it should be considered for introduction into nonendocrine chemotherapeutic regimens against human breast carcinomas and investigation in clinical trials [11].

References