دورية أكاديمية
أعرض في EDS

Causes and possibilities to circumvent cyclophosphamide toxicity.

التفاصيل البيبلوغرافية
العنوان: Causes and possibilities to circumvent cyclophosphamide toxicity.
المؤلفون: Voelcker G; Institute of Biochemistry II, Goethe University Frankfurt Medical School, Frankfurt, Germany.
المصدر: Anti-cancer drugs [Anticancer Drugs] 2020 Jul; Vol. 31 (6), pp. 617-622.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Lippincott Williams & Wilkins Country of Publication: England NLM ID: 9100823 Publication Model: Print Cited Medium: Internet ISSN: 1473-5741 (Electronic) Linking ISSN: 09594973 NLM ISO Abbreviation: Anticancer Drugs Subsets: MEDLINE
أسماء مطبوعة: Publication: London : Lippincott Williams & Wilkins
Original Publication: Oxford, UK : Rapid Communications of Oxford, [1990-
مواضيع طبية MeSH: Antineoplastic Agents, Alkylating/*toxicity , Cell Proliferation/*drug effects , Cyclophosphamide/*analogs & derivatives , Cyclophosphamide/*toxicity , Leukemia P388/*pathology , Phosphoramide Mustards/*toxicity, Animals ; Antineoplastic Agents, Alkylating/chemistry ; Cyclophosphamide/chemistry ; Female ; Leukemia P388/drug therapy ; Male ; Mice ; Phosphoramide Mustards/chemistry ; Toxicity Tests
مستخلص: Cyclophosphamide is an inert prodrug converted into 4-hydroxycyclophosphamide (OHCP) by hepatic hydroxylation. OHCP is in equilibrium with its tautomeric aldophosphamide (ALDO). From ALDO, the cytotoxic active metabolites are formed enzymatically by phosphodiesterases; these are the alkylating metabolite phosphoramide mustard (PAM) and the proapoptotic aldehyde 3-hydroxypropanal (HPA). PAM damages the DNA by alkylation; HPA amplifies the thereby induced apoptosis. The generally accepted view that acrolein, which is believed to be formed in the formation of PAM by β-elimination from ALDO would be mainly responsible for the toxicity of cyclophosphamide, has to be revised because no acrolein is formed in the systemic circulation of patients after cyclophosphamide administration. It is shown that not acrolein, but OHCP itself is the true toxic metabolite of cyclophosphamide. Toxicity tests with OHCP and PAM were carried out, which demonstrated that OHCP unfolds its toxicity, not as a carrier of PAM but is toxic itself by reacting with nucleophilic groups of macromolecules, for example, thiol groups of membrane proteins. Further experiments demonstrate that the toxicity of oxazaphosphorine cytostatics may be drastically reduced if the formation of the pharmacologically active metabolite ALDO bypasses the formation of OHCP. Toxicity experiments in mice with S-ethanol-cyclophosphamide (SECP) that hydrolyzes to OHCP show that SECP is as toxic as OHCP, whereas the thiazolidine of ALDO, which hydrolyzes to ALDO bypassing OHCP is 7-9 times less toxic without loss of antitumor activity.
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المشرفين على المادة: 0 (Antineoplastic Agents, Alkylating)
0 (Phosphoramide Mustards)
10159-53-2 (phosphoramide mustard)
1XBF4E50HS (4-hydroxycyclophosphamide)
7AM2ILM9FI (aldophosphamide)
8N3DW7272P (Cyclophosphamide)
تواريخ الأحداث: Date Created: 20200212 Date Completed: 20210308 Latest Revision: 20210308
رمز التحديث: 20231215
DOI: 10.1097/CAD.0000000000000912
PMID: 32044797
قاعدة البيانات: MEDLINE
الوصف
تدمد:1473-5741
DOI:10.1097/CAD.0000000000000912