Dược động học và dược lực học của 17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) trên chuột C.B-17 SCID mang tế bào ung thư vú người MDA-MB-231

Cancer Chemotherapy and Pharmacology - Tập 55 - Trang 21-32 - 2004
Julie L. Eiseman1,2, Jing Lan1,2, Theodore F. Lagattuta2, Deborah R. Hamburger2, Erin Joseph2, Joseph M. Covey3, Merrill J. Egorin1,2,4
1Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, USA
2Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, USA
3Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, USA
4Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, USA

Tóm tắt

17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) là một dẫn xuất tan trong nước của 17-(allylamino)-17-demethoxygeldanamycin (17AAG), một hợp chất hiện đang trong giai đoạn thử nghiệm lâm sàng. Các nghiên cứu tiền lâm sàng này: (1) xác định nồng độ 17DMAG trong huyết tương, mô bình thường và khối u sau khi tiêm tĩnh mạch vào chuột; và (2) liên hệ nồng độ 17DMAG trong khối u và mô bình thường với sự thay đổi của protein sốc nhiệt 90 (HSP90) và các protein được chaperone bởi HSP90. Tại những thời điểm nhất định sau khi tiêm tĩnh mạch 75 mg/kg 17DMAG, chuột SCID mang tế bào MDA-MB-231 được giết chết và huyết tương cùng mô được giữ lại. Nồng độ 17DMAG được xác định bằng phương pháp HPLC. Raf-1, protein sốc nhiệt 70 (HSP70) và HSP90 trong mô được xác định bằng phương pháp Western blotting. Nồng độ 17DMAG cao nhất trong huyết tương là 15.4±1.4 μg/ml. Diện tích dưới đường cong nồng độ 17DMAG trong huyết tương theo thời gian là 1072 μg/ml phút, tương ứng với độ thanh thải toàn thân là 70 ml/kg/phút. Nồng độ 17DMAG cao nhất trong gan (118.8±5.7 μg/g), thận (122.9±10.6 μg/g), tim (81.3±8.1 μg/g) và phổi (110.6±25.4 μg/g) đạt được sau 5–10 phút, trong khi nồng độ cao nhất trong lách (70.6±9.6 μg/g) và khối u (9.0±1.0 μg/g) đạt được sau 30–45 phút. Sau 48 giờ, 17DMAG có thể phát hiện được trong khối u nhưng không có trong bất kỳ mô bình thường nào. Raf-1 trong khối u của chuột được điều trị bằng 17DMAG đã chết ở 4, 7, 24 và 48 giờ thấp hơn khoảng 20% so với trong khối u của chuột được điều trị bằng dung môi. HSP90 và HSP70 trong khối u của động vật điều trị bằng 17DMAG thấp hơn đáng kể so với trong khối u của động vật đối chứng ở 4, 7 và 24 giờ. Hepatic Raf-1 giảm hơn 60% ở tất cả các thời điểm sau khi điều trị bằng 17DMAG; tuy nhiên, HSP90 gan không bị ảnh hưởng. HSP70 không thể phát hiện được trong gan của chuột điều trị bằng dung môi hoặc chuột chết ở 2 hoặc 4 giờ sau điều trị 17DMAG, nhưng được phát hiện trong gan ở 7, 24 và 48 giờ. 17DMAG không ảnh hưởng đến Raf-1 thận. Ngược lại, HSP70 và HSP90 thận giảm hơn 50% ở 2 và 4 giờ sau điều trị 17DMAG. HSP70 thận tăng khoảng gấp đôi so với trong thận của chuột đối chứng điều trị bằng dung môi ở 7 và 24 giờ, trong khi nồng độ protein tương đối của HSP90 không khác biệt so với đối chứng. Dược động học của 17DMAG trong chuột mang khối u tương tự như những gì đã được báo cáo trước đó trong chuột không mang khối u. 17DMAG phân bố rộng rãi đến các mô nhưng bị giữ lâu hơn trong khối u so với mô bình thường. Raf-1, HSP90 và HSP70 đã biến đổi ở các mức độ khác nhau trong khối u, gan và thận của động vật điều trị bằng 17DMAG. Những dữ liệu này minh họa tính chất phức tạp của các phản ứng sinh học đối với 17DMAG.

Từ khóa


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Cancer Chemotherapy and Pharmacology

Tập 55

21-32

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