Glufosfamide

383.16 g/mol

383.16

1W5N8SZD9A

C1612

141 Ų

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.

Kummerer K, et al; Chemosphere 40 (7): 767-73 (2000). The biodegradability of antineoplastic compounds in screening tests: influence of glucosidation and of stereochemistry.

Investigated for use/treatment in pancreatic cancer, solid tumors, breast cancer, colorectal cancer, brain cancer, lung cancer, ovarian cancer, and sarcoma.

... To determine the maximum-tolerated dose (MTD), the principal toxicities, and the pharmacokinetics of 6-hour infusion of glufosfamide (beta-D-glucosylisophosphoramide mustard; D-19575), a novel alkylating agent with the potential to target the glucose transporter system. ... Twenty-one patients (10 women and 11 men; median age, 56 years) with refractory solid tumors were treated with doses ranging from 800 to 6,000 mg/m(2). Glufosfamide was administered every 3 weeks as a two-step (fast/slow) intravenous infusion over a 6-hour period. All patients underwent pharmacokinetic sampling at the first course. ... The MTD was 6,000 mg/m(2). At this dose, two of six patients developed a reversible, dose-limiting renal tubular acidosis and a slight increase in serum creatinine the week after the second and third courses of treatment, respectively, whereas three of six patients experienced short-lived grade 4 neutropenia/leukopenia. Other side effects were generally mild. Pharmacokinetics indicated linearity of area under the time-versus-concentration curve against dose over the dose range studied and a short elimination half-life. There was clear evidence of antitumor activity, with a long-lasting complete response of an advanced pancreatic adenocarcinoma and minor tumor shrinkage of two refractory colon carcinomas and one heavily pretreated breast cancer. ... The principal toxicity of 6-hour infusion of glufosfamide is reversible renal tubular acidosis, the MTD is 6,000 mg/m(2), and the recommended phase II dose is 4, 500 mg/m(2). Close monitoring of serum potassium and creatinine levels is suggested for patients receiving glufosfamide for early detection of possible renal toxicity. Evidence of antitumor activity in resistant carcinomas warrants further clinical exploration of glufosfamide in phase II studies.

... /A study was conducted/ to determine the maximum tolerated dose (MTD)... and the pharmacokinetics of 6 hr infusion of glufosfamide ... a novel alkylating agent with the potential to target the glucose transporter system. Twenty-one patients (10 women, 11 men; median age 56 yr) with refractory solid tumors were treated with doses ranging from 800 to 6,000 mg/sq m. /The drug/ was admin very three weeks as a two step (fast/slow) iv infusion over a 6 hr period. All patients went under pharmacokinetic sampling at the first course. The MTD was 6,000 mg/sq m. ... Pharmacokinetics indicated linearity of the area the time-versus-concentration curve against dose over the dose range studied and a short elimination half life. ...

Beta-D-glucosyl-ifosfamide mustard (D 19575, glc-IPM, INN = glufosfamide) is a new agent for cancer chemotherapy. Its mode of action, which is only partly understood, was investigated at the DNA level. In the breast carcinoma cell line MCF7 glufosfamide inhibited both the synthesis of DNA and protein in a dose-dependent manner, as shown by the decreased incorporation of (3)H-methyl-thymidine into DNA and (14)C-methionine into protein of these cells. Treatment of MCF7 cells with 50 microM glufosfamide was sufficient to trigger poly(ADP-ribose) polymerase (PARP) activation, as revealed by immunofluorescence analysis. Both CHO-9 cells, which are O6-methylguanine-DNA methyltransferase (MGMT)-deficient, and an isogenic derivative, which has a high level of MGMT, showed the same cytotoxic response to beta-D-glc-IPM, indicating that the O6 position of guanine is not the critical target for cytotoxicity. By contrast, a sharp decrease in survival of cross-link repair deficient CL-V5 B cells was observed already at concentrations of 0.1 mM beta-D-glc-IPM, whereas the wild-type V79 cells showed a 90% reduction in survival only after treatment with 0.5 mM of this compound. The therapeutically inactive beta-L-enantiomer of glufosfamide also showed genotoxic effects in the same assays but at much higher doses. This was probably due to small amounts of ifosfamide mustard formed under the conditions of incubation. The results indicate that the DNA crosslinks are the most critical cytotoxic lesions induced by beta-D-glc-IPM.

/SRP:/ 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/|/SRP:/ 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/

... The objective of this study was to /compare/ the in vitro drug resistance proflile of glufosamide with other oxazaphosphorines in 106 samples of childhood acute leukemia by means of the MMT assay. The following drugs were tested: glufosfamide, 4-HOO-ifosfamide, 4-HOO-cyclophosphamide, mafosfamide cyclohexylamine salt, prednisolone, vincristine, L-asparaginase, daunorubicin and cytarabine. In this group of initial acute lymphoblastic leukemia (ALL) samples, equivalent cytotoxicity values for glufosfamide, 4-HOO-ifosfamide, 4-HOO-cyclophosphamide and mafosfamide were 5.95, 9.92, 4.60 and 3.90 ug/ml, respectively. In comparison to initial ALL samples, the relative resistance for glufosfamide and 4-HOO-ifosfamide in relapsed ALL samples were 1.9 (p= 0.049) and 1.3 (ns), and in initial acute myleoblastic leukemia (AML) samples, respectively, 31 (p< 0.001)and 5 (p= 0.001). All oxazaphosphorines showed highly significant cross resistance. In conclusion, glufosfamide is comparable to ifosfamide. Glufosfamide shows high activity against lymphoblasts both on diagnosis and relapse, however it cannot circumvent resistance to other oxazaphosphorines.|... /A study was conducted/ to determine the maximum tolerated dose (MTD), the principal toxicities, and the pharmacokinetics of 6 hr infusion of glufosfamide ... a novel alkylating agent with the potential to target the glucose transporter system. Twenty-one patients (10 women, 11 men; median age 56 yr) with refractory solid tumors were treated with doses ranging from 800 to 6,000 mg/sq m. /The drug/ was admin very three weeks as a two step (fast/slow) iv infusion over a 6 hr period. All patients went under pharmacokinetic sampling at the first course. The MTD was 6,000 mg/sq m. At this dose, two of six patients developed a reversible, dose limiting renal tubular acidosis and a slight incr in serum creatinine the week after the second and third courses of treatment, respectively, whereas three of six patients experienced short lived grade 4 neutropenia/leukopenia. ... The principal toxicity of the 6 hr infusion of glufosfamide is reversible renal tubular acidosis.

beta-D-Glc-IPM

Human drugs -> Rare disease (orphan)