ブスルファン

外観

白色～うすい黄色～うすい黄赤色粉末～結晶

用途

白血病の対症療法において使われる抗悪性腫瘍薬

用途

アルキル化剤です。DNAの合成、 複製を阻害し、細胞分裂抑制作用を示します。

効能

抗悪性腫瘍薬, アルキル化剤, 免疫抑制薬

商品名

ブスルフェクス (大塚製薬); マブリン (大原薬品工業)

説明

Chemically, busulfan is classified as an alkyl sulfonate. One or both of the methylsulfonate ester moieties can be displaced by the nucleophilic N7 of guanine, leading to monoalkylated and cross-linked DNA. The extent of alkyl sulfonate–mediated DNA interstrand cross-linking has been shown to vary with the length of the alkyl chain between sulfonate esters, with the tetramethylene-containing busulfan showing less interstrand cross-linking capability than hexamethylene, methylene, or octamethylene analogues. Intrastrand cross-linking also occurs, preferentially at 5′-GA-3′ but also at 5′-GG-3′ sequences. Alkylation of Cys sulfhydryl groups is yet another mechanism of cytotoxicity.

化学的特性

White Crystalline Solid

使用

Busulfan USP (Myleran) is used to treat Chronic granulocytic leukemia; other myeloproliferative disorders.

定義

ChEBI: A methanesulfonate ester that is butane-1,4-diol in which the hydrogens of the hydroxy groups are replaced by methanesulfonyl groups. An alkylating antineoplastic agent, it is used for the treatment of chronic myeloid leukemia (although it has been largely replaced by newer drugs). It is also used as an insect sterilant.

適応症

Busulfan (Myleran) is a bifunctional methanesulfonic ester that forms intrastrand cross-linkages with DNA. The drug is well absorbed after oral administration and has a plasma half-life of less than 5 minutes. Metabolites and degradation products are excreted primarily in the urine.
Busulfan is used in the palliative treatment of chronic granulocytic leukemia. Daily oral therapy results in decreased peripheral white blood cells and improved symptoms in almost all patients during the chronic phase of the disease. Excessive uric acid production from rapid tumor cell lysis should be prevented by coadministration of allopurinol.
At usual therapeutic dosages, busulfan is selectively toxic to granulocyte precursors rather than lymphocytes. Thrombocytopenia and anemia and less commonly, nausea, alopecia, mucositis, and sterility also may occur. Unusual side effects of busulfan include gynecomastia, a general increase in skin pigmentation, and interstitial pulmonary fibrosis.

一般的な説明

As an alternative to utilizing aziridines as electrophilic species,it was found that simply utilizing a carbon chain terminated atboth ends by leaving groups gave compounds capable of actingas cross-linking agents.Busulfan utilizestwo sulfonate functionalities as leaving groups separated by afour-carbon chain that reacts with DNA to primarily form intrastrandcross-link at 5'-GA-3' sequences.The sulfonatesare also subject to displacement by the sulfhydryl functionsfound in cysteine and glutathione, and metabolic products areformed as a result of nucleophilic attack by these groups togenerate sulfonium species along with methane sulfonicacid.This is followed by conversion to tetrahydrothiophene,and further oxidation products are subsequently produced togive the sulfoxide and sulfone. The cyclic sulfone known assulfolane may be further oxidized to give 3-hydroxysulfolane.

空気と水の反応

Busulfan is an alkylating agent which hydrolyzes in water. .

反応プロフィール

Busulfan is an alkylating agent which hydrolyzes in water. . Strong reducers may yield hydrogen sulfide.

危険性

Extremely toxic, carcinogen, clastogenic, teratogenic, immunosuppressive, delayed bone marrow aplasia, cataracts, pigmentation, pulmonary thrombosis, cardiotoxic effects, thrombocytopenia.

火災危険

Flash point data for Busulfan are not available. Busulfan is probably combustible.

臨床応用

Busulfan is used in the treatment of chronic myelogenous leukemia and can be administered either orally or by IV infusion.

副作用

Serious bone marrow hypoplasia and myelosuppression are possible with this agent, and recovery from busulfaninduced pancytopenia can take up to 2 years.

安全性プロファイル

Confirmed carcinogen producing leukemia, kidney, and uterine tumors. Experimental neoplastigenic and tumorigenic data. Poison by ingestion, subcutaneous, intraperitoneal, intravenous, and possibly other routes. Ingestion by pregnant women can cause cancer of the reproductive system of the fetus includtng the uterus. Human teratogenic effects by ingestion and possibly other routes include developmental abnormaltties of the eye, ear, craniofacial area including the nose and tongue, gastrointestinal system, endocrine system, urogenital system, and other unspecified areas. Other human reproductive effects by ingestion and possibly other routes include: impotence, changes in the uterus, cervix, and vagina, and menstrual-cycle dtsorders. Experimental reproductive effects. Human systemic effects by ingestion: general arteriolar or venous ddation of the eye, changes in structure or function of salivary glands. When heated to decomposition it emits toxic fumes of SOx. See also SULFONATES.

発がん性

1,4-Butanediol dimethanesulfonate is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.