Glufosfamide, 葡磷酰胺

Glufosfamide is a cytotoxic drug that is used in the treatment of some types of cancer. It is a prodrug that requires conversion to its active form, glufosfamid, by esterase enzymes before it can exert its genotoxic effects. Glufosfamide has shown to be active against platinum-resistant ovarian cancer and solid tumours. This drug also has been shown to inhibit the growth of prostate cancer cells and miapaca-2 cells, which are derived from pancreatic cancer. Glufosfamide has been found to have low toxicity in mice, but there may be adverse reactions when combined with other drugs such as erythromycin or ketoconazole.

Glufosfamide, also known as glucophosphamide, D-glucose isophosphoramide mustard, D-19575, is a new, experimental cytotoxic chemotherapeutic agent for treatment of malignancies. Glufosfamide is, basically, a glycosidic conjugate between β-D-glucose and the active alkylating moiety of the well-known antineoplasic drug ifosfamide, so-called "isophosphoramide mustard". Glufosfamide combines the active part of ifosfamide, a member of a widely used class of chemotherapy drugs known as "alkylators," with a glucose molecule. Because of its glucose component and a tumor cell's increased need for glucose, glufosfamide may be preferentially transported into tumors compared to most normal tissues. Inside cells, the linkage between glucose and the alkylator is cleaved to release the active drug.

Title: Glufosfamide

CAS Registry Number: 132682-98-5

CAS Name: 1-[N,N‘-Bis(2-chloroethyl)phosphorodiamidate]-b-D-glucopyranose

Additional Names: b-D-glucopyranosyl N,N’-di(2-chloroethyl) phosphoric acid diamide; b-D-glucosylisophosphoramide mustard

Manufacturers' Codes: D-19575

Molecular Formula: C10H21Cl2N2O7P

Molecular Weight: 383.16

Percent Composition: C 31.35%, H 5.52%, Cl 18.51%, N 7.31%, O 29.23%, P 8.08%

Literature References: Glucose coupled to isophosphoramide mustard, the active metabolite of the alkylating agent ifosfamide, q.v. Enters cells through upregulated glucose transport proteins. Prepn: M. Wiessler, M. Dickes, DE 3835772; eidem, US 5622936 (1990, 1997 both to Deutsches Krebsforschungszentrum Stiftung). Pharmacology and toxicity studies: J. Pohl et al., Cancer Chemother. Pharmacol. 35, 364 (1995). Mechanism of action study: H. Seker et al., Br. J. Cancer 82, 629 (2000). Clinical evaluation in pancreatic cancer: E. Briasoulis et al., Eur. J. Cancer 39, 2334 (2003); in non-small cell lung cancer: G. Giaccone et al., ibid. 40, 667 (2004). Review of pharmacology and clinical development: I. Niculescu-Duvaz, Curr. Opin. Invest. Drugs 3, 1527-1532 (2002).

Properties: LD50 in rats, mice (mg/kg): 1575, 1575 i.v.; 1470, 1470 orally (Pohl).

Toxicity data: LD50 in rats, mice (mg/kg): 1575, 1575 i.v.; 1470, 1470 orally (Pohl)

Therap-Cat: Antineoplastic.

Keywords: Antineoplastic; Alkylating Agents; Nitrogen Mustards.