Biological Half-Life
…A study aimed to determine the maximum tolerated dose (MTD)…and the pharmacokinetics of glutofuramide (a novel alkylating agent with potential targeting the glucose transport system) administered over a 6-hour infusion. Twenty-one patients with refractory solid tumors (10 women, 11 men; median age 56 years) received doses ranging from 800 to 6,000 mg/m². The drug was administered every three weeks via a two-step (rapid/slow) intravenous infusion over 6 hours. Pharmacokinetic sampling was performed on all patients at the first cycle. The MTD was 6,000 mg/m². …Pharmacokinetic results showed that the area under the concentration-time curve was linear with dose within the studied dose range, and the elimination half-life was short. …

[1]. Ex vivo responsiveness of head and neck squamous cell carcinoma to glufosfamide, a novelalkylating agent. Anticancer Res. 2004 Sep-Oct;24(5A):2947-51.

Glufosfamide is a compound formed by combining the mustard gas drug ifosfamide with glucose, exhibiting potential alkylating activity. Glufosfamide is cleaved by glucosidase in tumor cells to produce ifosfamide. Ifosfamide is subsequently alkylated and forms DNA cross-links, thereby inhibiting DNA replication and subsequent cell growth. The glucose moiety may enhance the uptake of the drug by tumor cells. Drug Indications It has been investigated for the treatment of pancreatic cancer, solid tumors, breast cancer, colorectal cancer, brain cancer, lung cancer, ovarian cancer, and sarcoma. Mechanism of Action β-D-glucosylifosfamide mustard (D 19575, glc-IPM, INN = glifoamide) is a novel chemotherapy drug for cancer. Its mechanism of action is not fully elucidated, but studies have been conducted at the DNA level. In the breast cancer cell line MCF7, glucosamine inhibited DNA and protein synthesis in a dose-dependent manner, manifested as a reduction in (3)H-methylthymidine incorporation into DNA and (14)C-methionine incorporation into proteins. Immunofluorescence analysis showed that treatment of MCF7 cells with 50 μM glucosamine was sufficient to activate poly(ADP-ribose) polymerase (PARP). CHO-9 cells lacking O6-methylguanine-DNA methyltransferase (MGMT) and their MGMT-overexpressing homologous derivatives showed the same cytotoxic response to β-D-glucosidase-isopyridine (β-D-glc-IPM), indicating that the O6 site of guanine is not a key target for cytotoxicity. In contrast, at a concentration of 0.1 mM β-D-glc-IPM, the survival rate of crosslink repair-deficient CL-V5 B cells was significantly reduced, while the survival rate of wild-type V79 cells only decreased by 90% after treatment with 0.5 mM of the compound. In the same experiment, non-therapeutic β-L-enantiomer glutamine also showed genotoxicity, but required higher doses. This is likely due to the generation of small amounts of ifosfamide mustard under incubation conditions. The results indicate that DNA cross-linking is the most critical cytotoxic damage induced by β-D-glucosylisophosphoramide (β-D-glc-IPM).

---

Therapeutic Use
…To determine the maximum tolerated dose (MTD), major toxicities, and pharmacokinetics of the novel alkylating agent glutofamide (β-D-glucosylisophosphoramide mustard; D-19575) administered over a 6-hour infusion, glutofamide has the potential to target the glucose transport system. …Twenty-one patients with refractory solid tumors (10 women, 11 men; median age 56 years) were treated with doses ranging from 800 to 6000 mg/m². Glufosamide was administered every 3 weeks via a two-step (fast/slow) intravenous infusion over 6 hours. Pharmacokinetic sampling was performed on all patients at the start of the first cycle. The maximum tolerated dose (MTD) was 6,000 mg/m². At this dose, two out of six patients experienced reversible dose-limiting renal tubular acidosis and a mild increase in serum creatinine one week after the second and third cycles, respectively, while three out of six patients experienced transient grade 4 neutropenia/leukopenia. Other side effects were generally mild. Pharmacokinetic studies showed that the area under the concentration-time curve was linear with the dose within the studied dose range, and the elimination half-life was short. Evidence of antitumor activity was clear, with one patient achieving durable complete remission in advanced pancreatic adenocarcinoma, and two patients with refractory colon cancer and one patient with previously heavily treated breast cancer showing slight tumor shrinkage. ...The main toxicity of 6-hour ghrelin infusion was reversible renal tubular acidosis. The maximum tolerated dose (MTD) was 6,000 mg/m², and the recommended phase II dose was 4,500 mg/m². It is recommended that patients receiving glutofuramide treatment be closely monitored for serum potassium and creatinine levels in order to detect potential nephrotoxicity early. Glufosfamide has shown antitumor activity in drug-resistant cancers, therefore, further exploration of its clinical application in phase II studies is necessary.

C10H21CL2N2O7P

383.16

382.046

132682-98-5

123628

Typically exists as solid at room temperature

1.6±0.1 g/cm3

569.9±60.0 °C at 760 mmHg

298.5±32.9 °C

0.0±3.6 mmHg at 25°C

1.563

-1.07

6

9

9

22

369

5

O[C@@H]1[C@@H](O)[C@H](OP(NCCCl)(NCCCl)=O)O[C@H](CO)[C@H]1O

PSVUJBVBCOISSP-SPFKKGSWSA-N

InChI=1S/C10H21Cl2N2O7P/c11-1-3-13-22(19,14-4-2-12)21-10-9(18)8(17)7(16)6(5-15)20-10/h6-10,15-18H,1-5H2,(H2,13,14,19)/t6-,7-,8+,9-,10+/m1/s1

(2S,3R,4S,5S,6R)-2-bis(2-chloroethylamino)phosphoryloxy-6-(hydroxymethyl)oxane-3,4,5-triol

D 19575 D-19575 D19575

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~125 mg/mL (~326.23 mM)

Solubility in Formulation 1: 50 mg/mL (130.49 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

---

 (Please use freshly prepared in vivo formulations for optimal results.)