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解説
シクロホスファミド,ビス(2-クロロエチル)アミンにオキシ塩化リンを反応させ，次に2-アミノプロパン-1-オールと環化させると得られる．ラセミ体は無色の柱状晶．融点51～52 ℃．一水和物は融点41 ℃．(R)-シクロホスファミドは融点65～66 ℃，[α]20D ＋2.3°(メタノール)．酢酸に易溶，エタノール，ベンゼン，水に可溶．多発性骨髄腫，悪性リンパ腫，乳がん，急性白血病，肺がん治療薬として使用される．LD50 421 mg/kg(マウス，静注)．シクロホスファミド,ナイトロジェン・マスタード誘導体の一種。核酸やその他の細胞構成成分をアルキル化して細胞の代謝を阻害し，特に腫瘍細胞を死にいたらしめる。こうした作用をもつ抗腫瘍剤をアルキル化剤と呼んでいる。それ自体に抗腫瘍性はなく，生体内で開環されて活性物質となる。腫瘍細胞に対する選択性は高い。安全域は高く，急性毒性はナイトロジェンマスタード-N-オキシドの約2分の1で，慢性毒性もアルキル化剤のなかでは最も低い。各種の肉腫，ホジキン病，白血病，各種の悪性腫瘍などの改善に用いる。副作用として白血球減少，頭痛，胃腸障害，脱毛，出血傾向などがみられるが他のアルキル化剤より少い。
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用途
抗悪性腫瘍薬、副腎皮質ステロイド及びビンクリスチンとの併用でホジキン病と非ホジキンリンパ腫の治療、小児の慢性リンパ球性白血病、慢性顆粒球白血病、急性骨髄性、単芽球性白血病及び急性リンパ芽球白血病、多発性骨髄腫、菌状息肉腫、神経芽細胞腫、卵巣腺癌、網膜芽腫、乳癌及び特定の肺がん。
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効能
抗悪性腫瘍薬, アルキル化剤
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化学的特性
Endoxan is a white crystalline powder (monohydrate). It may be used or shipped in solution. Darkens on
exposure to light. Odorless
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使用
Cyclophosphamide USP is used to treat acute and chronic lymphocytic leukemia; lung cancer; rhabdomyosarcoma; neuroblastoma; ovarian and mammary carcinoma; multiple myeloma; lymphosarcoma; Burkitt’s lymphoma; Hodgkin’s disease; retinoblastoma; mycosis fungoides
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適応症
Cyclophosphamide (Cytoxan) is the most versatile and
useful of the nitrogen mustards. Preclinical testing
showed it to have a favorable therapeutic index and to
possess the broadest spectrum of antitumor activity of
all alkylating agents. As with the other nitrogen mustards,
cyclophosphamide administration results in the
formation of cross-links within DNA due to a reaction
of the two chloroethyl moieties of cyclophosphamide
with adjacent nucleotide bases. Cyclophosphamide
must be activated metabolically by microsomal enzymes
of the cytochrome P450 system before ionization
of the chloride atoms and formation of the cyclic
ethylenimmonium ion can occur. The metabolites
phosphoramide mustard and acrolein are thought to be
the ultimate active cytotoxic moiety derived from
cyclophosphamide.
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定義
ChEBI: Cyclophosphamide is a phosphorodiamide that is 1,3,2-oxazaphosphinan-2-amine 2-oxide substituted by two 2-chloroethyl groups at the amino nitrogen atom. It is an alkylating agent used in the treatment of several forms of cancer including leukemias, lymphomas and breast cancer.
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一般的な説明
Cyclophosphamide is a fine white crystalline powder. Odorless with a slightly bitter taste. Melting point 41-45 °C. A 2% solution has pH of 4 to 6. Used medicinally as an antineoplastic agent.
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空気と水の反応
Water soluble.
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反応プロフィール
Cyclophosphamide is sensitive to exposure to light (darkens). Also sensitive to oxidation. Aqueous solutions may be kept for a few hours at room temperature, but hydrolysis occurs at temperatures above 86°F. Solutions in DMSO, 95% ethanol or acetone are stable for 24 hours under normal lab conditions. Incompatible with benzyl alcohol. Undergoes both acid and base hydrolysis at extreme pHs
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火災危険
Flash point data for Cyclophosphamide are not available; however, Cyclophosphamide is probably combustible.
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作用機序
Cyclophosphamide can be given orally, intramuscularly,
or intravenously. The plasma half-life of intact cyclophosphamide
is 6.5 hours.Only 10 to 15% of the circulating
parent drug is protein bound, whereas 50% of
the alkylating metabolites are bound to plasma proteins.
Since cyclophosphamide and its metabolites are
eliminated primarily by the kidneys, renal failure will
greatly prolong their retention.
Cyclophosphamide has a wide spectrum of antitumor
activity. In lymphomas, it is frequently used in combination
with vincristine and prednisone (CVP [or
COP] regimen) or as a substitute for mechlorethamine
in the MOPP regimen (C-MOPP). High dosages of intravenously
administered cyclophosphamide are often
curative in Burkitt’s lymphoma, a childhood malignancy
with a very fast growth rate.Oral daily dosages are useful
for less aggressive tumors, such as nodular lymphomas,
myeloma, and chronic leukemias.
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薬理学
Besides being used as an alkylating agent in cancer chemotherapy, cyclophosphamide is a
unique drug when used as an immunosuppressant. First, it is the most powerful of all such
drugs. Second, it kills proliferating cells, and evidently alkylates a certain region of remaining cells. Finally, its action on T-cells is such that despite its overall suppressive
effect, it can, in certain environments, suppress the response of these cells to antigens.
Cyclophosphamide is successfully used for bone transplants. In small doses, it is effective
for autoimmune disorders.
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薬物動態学
The drug is metabolized in the liver and is eliminated via the kidney, with approximately 15% of a given dose being excreted unchanged. Doses should be reduced in patients with levels of creatinine clearance less than 30 mL/min. Interestingly, hepatic dysfunction does not seem to alter metabolism of this drug, but caution should be exercised in patients with inhibited cytochrome P450 (CYP450) enzymes or with a combination of factors that could negatively impact drug activation/inactivation pathways.
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臨床応用
Cyclophosphamide is a component of CMF (cyclophosphamide,
methotrexate, 5-fluorouracil) and
other drug combinations used in the treatment of breast
cancer. Cyclophosphamide in combination may produce
complete remissions in some patients with ovarian
cancer and oat cell (small cell) lung cancer. Other tumors
in which beneficial results have been reported include
non–oat cell lung cancers, various sarcomas, neuroblastoma,
and carcinomas of the testes, cervix, and
bladder. Cyclophosphamide also can be employed as an
alternative to azathioprine in suppressing immunological
rejection of transplant organs.
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副作用
Chloroacetaldehyde toxicity is accompanied by glutathione depletion, indicating that, as expected, this electrophilic by-product alkylates Cys residues of critical cell proteins. Alkylation of Lys, adenosine, and cytidine residues also is possible. The CYP-generated carbinolamine undergoes nonenzymatic hydrolysis to provide the aldophosphamide either in the bloodstream or inside the cell. If this hydrolysis occurs extracellularly, the aldophosphamide is still able to penetrate cell membranes to reach the intracellular space. Once inside the cell, acrolein (a highly reactive α,β-unsaturated aldehyde) splits off, generating phosphoramide mustard. With a pKa of 4.75, the mustard will be persistently anionic at intracellular pH and trapped inside the cell.
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安全性プロファイル
Confirmed human
carcinogen producing leukemia, Hodgkin's
dsease, gastrointestinal and bladder tumors. Experimental carcinogenic, neoplas tigenic,
and teratogenic data. A human poison by
ingestion and many other routes. Human
systemic effects: hdney changes (hepatic
dysfunction), leukopenia (reduced white
blood cell count), nausea and alopecia (loss
of hair), liver changes, agranulocytosis.
Human reproductive and teratogenic effects
by multiple routes: spermatogenesis,
testicular changes, epiddymis and sperm
duct changes, menstrual cycle changes, fetal
developmental abnormahties of the
craniofacial area, musculoskeletal and
cardiovascular systems. Experimental
reproductive effects. Human mutation data
reported. A powerful skin irritant. Used as
an immunosuppressive agent in
nonmalignant diseases. When heated to
decomposition it emits hghly toxic fumes of
PO,, NOx, and Cl-.
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職業ばく露
Exodan is used as an immunosuppressive agent in nonmalignant diseases; treatment of malignant
lymphoma, multiple meyloma; leukemias, and other malignant diseases. Exodan has been tested as an insect chemosterilant and for use in the chemical shearing of sheep.
Exodan is not produced in the United States.; manufactured
in Germany and imported into the United States since1959.
The FDA estimates that 200,000300,000 patients per year
are treated with exodan. It is administered orally and
through injection. The adult dosage is usually 15 mg/kg
of body weight daily or 1015 mg/kg administered intravenous every 710 days
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発がん性
Cyclophosphamide is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.
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代謝
The initial metabolic step is mediated primarily by CYP2B6 (and, to a much lower extent, by CYP3A4) and involves hydroxylation of the oxazaphosphorine ring to generate a carbinolamine. This hydroxylation reaction must occur before the molecule will be transported into cells. CYP3A4 (but not CYP2B6) also catalyzes an inactivating N-dechloroethylation reaction, which yields highly nephrotoxic and neurotoxic chloroacetaldehyde.
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輸送方法
UN3464 Organophosphorus compound, solid,
toxic, n.o.s, Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required.
UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1;
Labels: 6.1-Poisonous materials, Technical Name Required.
UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1;
Labels: 6.1-Poisonous materials. UN1851 Medicine, liquid,
toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous
materials
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不和合性
Should be protected from exposure to
temperatures above 30°C/86°F.
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廃棄物の処理
Consult with environmental
regulatory agencies for guidance on acceptable disposal
practices. Generators of waste containing this contaminant
(≥100 kg/mo) must conform with EPA regulations governing storage, transportation, treatment, and waste disposal
