ビンクリスチン

ビンクリスチン 化学特性,用途語,生産方法

• 解説

  ビンクリスチン，融点218～220 ℃．[α]²⁵_D＋17°(ジクロロエタン)．pKa 5.0，7.4(DMF)．硫酸塩は分解点273～281 ℃．水，メタノールに易溶．λmax 220，255，296 nm(エタノール)．急性白血病，悪性リンパ腫治療薬として使用される．
  森北出版「化学辞典（第2版）

• 成分

  ビンクリスチン，ロイコクリスチンともいう．ニチニチソウCatharanthus roseusに微量含まれる二量体アルカロイド．

• 用途

  急性白血病，悪性リンパ腫治療薬として使用される．

• 効能

  抗悪性腫瘍薬, 微小管重合阻害薬

• 毒性

  LD50 2.2 mg/kg(マウス，静注)．

• 説明

  A complex dimeric alkaloid isolated from Vinca minor, this base has the structure given above based upon chemical and spectroscopic data. It resembles Vinblastine in its pharmacological action. Depending on the dosage, it causes either thrombocytosis with no effect upon the leucocytes, or thrombocytopenia accompanied by peucopenia in rats. Thrombocytosis persists even after prolonged treatment with drugs given in the correct dosage.

• 化学的特性

  solid

• 物理的性質

  Appearance: needlelike crystals were produced when recrystallized by methanol. The other properties of vincristine are similar to vinblastine.

• 来歴

  Vinblastine and vincristine were extracted from vinca, and researchers found that they are the main ingredient of vinca which have antitumor activity. This is an accidental harvest by hard work and inspiration during scientific research process. It was firstly reported as an important discovery by Annals of the New York Academy of Sciences, and one report was published by Robert Noble and Charles Thomas Beer . They demonstrated that vinblastine can cause severe leukopenia. In 1963, vincristine (trade name, Oncovin) developed by Eli Lilly was approved by the US FDA, it provided a good choice for tumor chemotherapy program and gradually became the essential tumor chemotherapy drugs.
  At the early stages of the study, vinblastine and vincristine are directly extracted from the vinca, but the cost is high, and the extraction efficiency is low . Especially the specific chiral monomer compounds with biological activity are difficult to obtain. In the following years, the researchers used genetic engineering, biosynthesis, chemical synthesis, and other technical methods to explore and optimize the production process of vinblastine drugs. In particular, the rise of asymmetric synthesis provides a more economical choice for the synthesis of vinblastine compounds and increases productivity to more than 22% . At the same time, the pharmaceutical dosage forms were developed from the beginning as simple sulfate injection to liposomal preparations and nanoparticle preparations, which improve the efficacy, reduce adverse reactions, and play better antitumor effect.

• 使用

  Antineoplastic[Note—Graphic formula same as for Vinblastine Sulfate, except that R is CHO].

• 適応症

  It was recorded in the Pharmacopoeia of the People’s Republic of China (2015), the British Pharmacopoeia (2017), the United States Pharmacopeia (40), the Japanese Pharmacopoeia (17th ed.), the European Pharmacopoeia (9th ed.), and The International Pharmacopoeia (5th ed.).
  Vincristine sulfate injection is used to treat leukemia, lymphadenoma, non-small cell lung cancer, nephroblastoma, and neuroblastoma in clinical practice generally, but the effect of vinblastine is better than vincristine in Hodgkin lymphoma treatment.

• 一般的な説明

  A white crystalline solid. Melting point 218°C. Used as an antineoplastic.

• 健康ハザード

  Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution.

• 火災危険

  Flash point data for Vincristine are not available, but Vincristine is probably combustible.

• 薬理学

  Vinblastine drugs have a strong inhibitory effect on monozygotic leukemia, breast cancer, liver cancer, ovarian cancer, head and neck cancer, testicular cancer, solid sarcoma, and malignant melanin in a variety of spontaneous or transplanted lymphocytic leukemias. Although the structure of vinblastine and vincristine is very similar, there are some differences in pharmacological effects, and there is no crossresistance .
  The mechanism of vinblastine and vincristine is similar as cell cycle-specific antineoplastic agents. They all inhibit tubulin polymerization, interfere spindle microtubule formation, block the cell cycle in M phase, and then inhibit the proliferation of cancer cells . X-ray diffraction results showed that Vinblastine targets at the hydrophobic structure on tubulin, Vinblastine inserted into the trough as the wedge, blocking the polymerization of tubulin, making a spirochete structure of tubulin itself form, and loss of biological role . However, this antitumor effect can affect other rapid proliferation cells, and then small intestinal epithelial cells and bone marrow cells will be inhibited, which is one of the reasons of gastrointestinal side effects and bone marrow transplantation side effects. The effect of vincristine is better than vinblastine, and the dosage is lower, the probability and intensity of side effects are lower. Recently, it has been found that vinblastine and vincristine can also suppress growth of tumor cell by inhibiting the synthesis of RNA and protein.

• 臨床応用

  Vincristine is an important component of the curative combination chemotherapy for acute lymphoblastic leukemia, Hodgkin’s disease (the MOPP regimen), and non-Hodgkin’s lymphomas. It is also used in several regimens for pediatric solid tumors, including Wilms’ tumor, Ewing’s sarcoma, rhabdomyosarcoma, and neuroblastoma; in adult tumors of the breast, lung, and cervix; and in sarcomas. Its relative lack of myelosuppression makes it more attractive than vinblastine for use in combination with myelotoxic drugs.Vinblastine is especially useful in testicular carcinomas and is also active in Hodgkin’s disease, other types of lymphomas, breast cancer, and renal cell carcinoma.

• 副作用

  All vinca alkaloids are severe vesicants that can induce necrosis, cellulitis, and/or thrombophlebitis. Proper needle placement before administration should be assured to eliminate the risk of extravasation. Unlike the tissue damage caused by the vesicant action of nitrogen mustards and antibiotic antineoplastics, cold exacerbates tissue destruction. If extravasation occurs, apply heat for 1 hour fours time a day for 3 to 5 days, coupled with local hyaluronidase injections. Vinca alkaloids are all Category D teratogens and are fatal if administered by the intrathecal route.

• 参考文献

  Mokry et al., Experientia, 18, 564 (1962) Pharmacology: Chandorkar.,lnd. J. Physiol. Pharmacol., 17, 105 (1973)

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