Treosulfan

278.29

278.30

206-081-0

260698|39069|39068

DTXSID0026173

L01AB02|L - Antineoplastic and immunomodulating agents

144

-1.64

Treosulphan is an odorless white crystalline powder. (NTP, 1992)

1.6±0.1 g/cm3

76-78 °C

607.0±55.0 °C at 760 mmHg

320.9±31.5 °C

1.518

greater than or equal to 100 mg/mL at 66° F (NTP, 1992)

0mmHg at 25°C

LDLo intravenous in dog: 222mg/kg

III

6.1(b)

UN 2811

P201, P202, P260, P264, P270, P281, P308+P313, P309+P311, P405, P501

H350

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

L-buthionine-[S,R]-sulfoximine had minor effects on the toxicity of doxorubicin, ACNU (1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosou rea, nimustine) and vincristine. L-buthionine-[S,R]-sulfoximine failed to alter teniposide or cytarabine toxicity. L-buthionine-[S,R]-sulfoximine induced prominent sensitization to the alkylating agent, treosulfan, in both cell lines, as assessed by viability assays, in situ DNA end labeling and quantitative DNA fragmentation. Treosulfan is thought to mediate toxicity via formation of reactive epoxides.

Treosulfan in combination with fludarabine is indicated as part of conditioning treatment prior to allogeneic haematopoietic stem cell transplantation (alloHSCT) in adult patients with malignant and non malignant diseases, and in paediatric patients older than one month with malignant diseases.,|Conditioning treatment prior to haematopoietic-progenitor-cell transplantation

Therapy of advanced renal cell carcinoma remains difficult. New therapeutic schemes besides cytokine treatment should be evaluated. The following study analyzes the in vitro toxicity of treosulfan on spheroids of 8 primary cultures of renal cell carcinoma cells. these data were compared to the toxicity of vinblastine. All investigations were performed in regard to the P-glycoprotein (Pgp) expression of the cells, which is one of the main causes of multidrug resistance. Four Pgp positive and four Pgp negative spheroids were incubated with the drugs in increasing doses. Toxicity was measured using the MTT toxicity assay as well as trypan blue exclusion. Significantly higher toxicity of treosulfan compared to vinblastine could be demonstrated. In addition, the effects of treosulfan were not related to Pgp expression. These results are encouraging and a phase II study analyzing the efficacy of treosulfan in patients with advanced renal cell carcinoma has been initiated in our institution.|[Schmidt F et al; J Neurooncol 49 (3): 231-4 (2000)] Treosulfan is a bifunctional alkylating prodrug with activity against various solid tumors. To improve the outcome for patients with recurrent malignant glioma, we assessed the efficacy of intravenous treosulfan (6-10 g/m2 4-weekly) as salvage therapy for patients with recurrent or progressive glioblastoma (GB, n = 14) or anaplastic astrocytoma (AA, n = 2). All patients had prior involved-field radiotherapy and adjuvant nitrosourea-based chemotherapy. A total of 56 cycles were administered. Tumor responses were assessed radiologically and clinically prior to each cycle. All patients were assessable for toxicity, response and survival. There were no complete or partial responses (CR, PR). Two patients progressed after the first cycle, 14 patients had initially stable disease (SD). Median progression-free survival was 3.25 months for the glioblastoma patients. Five patients were progression-free at 6 months (30%), including the 2 anaplastic astrocytoma patients. The 2 anaplastic astrocytoma patients are stable at 22 months. ... Treosulfan has modest activity in patients with recurrent malignant glioma. Further evaluation of treosulfan in chemonaive malignant glioma patients is warranted.

Myelosuppression was the dose-limiting toxicity in this cohort of nitrosourea-pretreated patients.|Acute non-lymphocytic leukemia occurred in eight women following long-term treatment with Treosulfan (= dihydroxybusulfan) for ovarian carcinoma. The leukemia developed from 21 to 58 months (median 50 months) after the institution of chemotherapy. At the time when the leukemia appeared seven of the patients were in complete, and one in partial, remission as regards the ovarian carcinoma. Seven of the eight cases of acute leukemia occurred in a series of 553 patients treated with Treosulfan for ovarian cancer in the period from 1970 to 1977 and followed closely for a total of 1159 patient-years up to February 1978. As compared with an expected number of 0.04 cases of acute myeloblastic leukemia based on patient-years, the observed seven cases correspond to a 175-times increased risk. Although the cumulative probability of acute non-lymphocytic leukemia among surviving patients at five years using life-table statistics was 7.6%, the survival curve for the 553 patients with ovarian carcinoma was only slightly affected by death from leukemia. The probability of developing acute leukemia in this study was not significantly correlated to the total cumulative dosage of Treosulfan. Cytogenetic studies of the bone marrow performed after the development of acute leukemia showed chromosome abnormalities in all five patients examined, with hypodiploidy and loss of B and C group chromosomes.|Treosulfan and busulphan are similar molecules, the former used in the treatment of ovarian cancer and the latter in chronic myelogenous leukaemia. We have used both in the differential staining cytotoxicity (DiSC) assay for in vitro drug sensitivity testing to aid in the choice of chemotherapy for individual patients. It was observed that occasionally the viability of control cells in one assay box was reduced compared with control cells in other boxes from the same assay. Treosulfan was suspected as the cause because cells throughout the microtitre box containing treosulfan had reduced viability in 28/62 (45%) experiments and in 9 of these, total kill of all cells in the box was observed. We tested the hypothesis that a metabolite of treosulfan might be the cause of this airborne cytotoxicity, and found that whilst 10 mg ml-1 of either methane sulphonic acid or tetrahydrofuran had no airborne cytotoxic effect, 1 mg ml-1 diepoxybutane killed over 95% of cells in all tubes in the same box. Treosulfan is another chemical (cf. azide, mafosfamide and possibly other cytotoxic agents) that can cause airborne cytotoxicity.

A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026) (See all compounds classified as Antineoplastic Agents, Alkylating.)

In a pharmacologic study of the bioavailability of treosulfan in a capsule formulation, patients with relapsed ovarian carcinoma were treated with alternating doses of oral and intravenous (i.v.) treosulfan of 1.5 or 2.0 g daily for 5 to 8 days. ... The bioavailability ratio (f) of oral to i.v. administration was calculated as 0.97 + or - 0.18 (mean + or - SD) using the values AUC oral = 82.1 + or- 39.4 ug/ml hr and AUC i.v. = 85.4 + or - 30.3 ug/ml hr. The peak plasma concentration cmax (29 + or - 14 ug/ml vs 65 + or - 23 ug/ml) was significantly (P < 0.01) higher after i.v. administration and the tmax after oral administration was 1.5 + or - 0.34 hr. The terminal half-life of treosulfan was about 1.8 hr. The mean urinary excretion of the parent compound was about 15% of the administered total dose over 24 hr (range 6-26%). ... A feasible and reliable oral treosulfan formulation could provide the basis for the development of long-term low-dose outpatient treatment of patients with malignant diseases.

The anti-tumour drug treosulfan (L-threitol 1,4-bismethanesulphonate, Ovastat) is a prodrug for epoxy compounds by converting non-enzymatically to L-diepoxybutane via the corresponding monoepoxide under physiological conditions. The present study supports the hypothesis that this conversion of treosulfan is required for cytotoxicity in vitro. DNA alkylation and interstrand cross-linking of plasmid DNA is observed after treosulfan treatment, but this is again produced via the epoxide species. Alkylation occurs at guanine bases with a sequence selectivity similar to other alkylating agents such as the nitrogen mustards. In treosulfan-treated K562 cells, cross-links form slowly, reaching a peak at approximately 24 h. Incubation of K562 cells with preformed epoxides shows faster and more efficient DNA cross-linking.

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

... Twenty-two patients (15 ovarian and 7 other carcinomas/lymphomas) with a median age of 48 years were treated with 28 high-dose courses. Treosulfan was infused over 2 hr at escalating doses from 20 to 56 g/sq m, and pharmacokinetic parameters were analyzed. At 56 g/sq m, three of six patients experienced dose-limiting toxicities: diarrhea grade III/IV in three patients; mucositis/stomatitis grade III in one patient; toxic epidermal necrolysis in one patient; and grade III acidosis in one patient. Other low-grade side effects, including erythema, pain, fatigue, and nausea/vomiting, were recorded. Two patients died within 4 weeks after treatment because of rapid tumor progression and fungal infection, respectively. Plasma half-life, distribution volume, and renal elimination of treosulfan were independent of dose, whereas the increase in area under the curve was linear up to 56 g/sq m treosulfan. The maximum tolerated dose of high-dose treosulfan is 47 g/sq m. A split-dose or continuous infusion regimen is recommended for future high-dose trials. 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.|Venous blood was taken from apparently healthy volunteers and patients with cancer, the latter both before and at intervals after treatment with single cytotoxic drugs. Cells from untreated individuals were exposed to a range of concentrations of drugs in culture medium. Chlorambucil, treosulfan and cyclophosphamide (activated by hepatic microsomes) significantly increased the numbers of SCEs, both in vitro and in the lymphocytes of patients. While methotrexate and 5-fluorouracil had no effect, bleomycin slightly increased the number of SCEs, but only in vitro. Although the in vitro dose-effect relationship indicated which drugs would increase the frequency of SCE in vivo, the magnitude of the response tended to be overestimated. When patients were treated with drugs the frequency of SCE increased, then declined with time. Though this complicates the quantitative relationship between dose and damage, SCEs may be useful to monitor the effects of alkylating agents on normal tissues.

L-dihydroxybusulfan

Treosulfan (L-threitol-1,4-bis-methanesulfonate, Ovastat) is a prodrug of a bifunctional alkylating agent with activity in ovarian carcinoma and other solid tumors. In a pharmacologic study of the bioavailability of treosulfan in a capsule formulation, patients with relapsed ovarian carcinoma were treated with alternating doses of oral and intravenous (i.v.) treosulfan of 1.5 or 2.0 g daily for 5 to 8 days. A sensitive method for the determination of treosulfan in plasma and urine by reversed-phase high-performance liquid chromatography had previously been developed. Pharmacokinetic analyses of treosulfan were carried on plasma and urine samples from 20 i.v. courses and 20 courses of oral administration. The bioavailability ratio (f) of oral to i.v. administration was calculated as 0.97 + or - 0.18 (mean + or - SD) using the values AUC oral = 82.1 + or- 39.4 ug/ml hr and AUC i.v. = 85.4 + or - 30.3 ug/ml hr. The peak plasma concentration cmax (29 + or - 14 ug/ml vs 65 + or - 23 ug/ml) was significantly (P < 0.01) higher after i.v. administration and the tmax after oral administration was 1.5 + or - 0.34 hr. The terminal half-life of treosulfan was about 1.8 hr. The mean urinary excretion of the parent compound was about 15% of the administered total dose over 24 hr (range 6-26%). The high and relatively constant bioavailability of treosulfan indicates that capsules provide a satisfactory noninvasive treatment alternative. A feasible and reliable oral treosulfan formulation could provide the basis for the development of long-term low-dose outpatient treatment of patients with malignant diseases.|Treosulfan (L-threitol- 1,4-bis-methanesulfonate, Ovastat) is a prodrug of a bifunctional alkylating agent with activity in ovarian carcinoma and other solid tumors. For a clinical and pharmacology study, patients with advanced, refractory, or resistant solid tumors were treated with a single-dose intravenous 30-min infusion of 8 or 10 g/sq m treosulfan. A sensitive method for the determination of treosulfan in plasma and urine by reverse-phase high-performance liquid chromatography was developed. A total of 14 plasma and urine treosulfan pharmacokinetics determinations were analyzed in the 8-g/sq m group and 7 were analyzed in the 10-g/sq m group, the maximum tolerated dose for this group of pretreated patients. The terminal half-life of treosulfan was in the range of 1.8 hr. AUC and Cmax values were significantly (P < 0.01) higher in the 10-g/sq m group (AUC 708 + or - 168 versus 977 + or - 182 microg ml(-1) hr, Cmax 465 + or -98 versus 597 + or - 94 ug/ml). The mean urinary excretion of the parent compound was about 25% of the total dose delivered over 48 hr (range 5-49%), and about 20% was excreted during the first 6 hr after administration. Currently, a clinical phase I pharmacokinetics and dose-escalation trial with autologous blood stem-cell support has been started at 20 g/sq m treosulfan using a 2-hr infusion protocol

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