基本信息
浏览量:297
职业迁徙
个人简介
Research Interests
drug development using radiolabeled thymidine analogs, liposomes, and other drugs using PET
imaging cellular proliferation and stress in vivo
testing response to drug therapy for cancer
Research Description
Drug Discovery and Development
The ultimate goal of our research is to understand the response of cancer to therapy using measurements of DNA synthetic pathways as imaged by positron emission tomography (PET). Ongoing studies have refined the techniques needed to obtain PET images with radiolabeled thymidine analogs, which are trapped in the DNA synthetic pathway. Studies that began in tissue culture and mice have now progressed to clinical trials. We have addressed a number of the problems associated with interpreting the PET images including the contributions to thymidine metabolism of intracellular pools, reutilization, and degradation. The most promising compound we have used to date is 18F-FLT (3'-deoxy-3'- fluorothymidine), which is an antiviral compound like AZT. It is trapped intracellularly after phosphorylation by thymidine kinase (TK) in a manner similar to the trapping of glucose analogs (FDG) after phosphorylation by hexokinase. This compound is stable to degradation and undergoes little metabolism, aside from glucuronidation. Studies in dogs and patients indicate that it readily visualizes proliferating organs such as the bone marrow, as well as tumors. Another analog, 18F-FMAU {1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-thymine} is being studied in cell culture, animals and humans. Our in human studies found that FMAU was readily retained in tumors, but not in normally prolferating bone marrow. FMAU is retained by the action of thymidine kinase 2 (TK2), a mitochondrial enzyme. We have found that increased retention reflects cellular stress. This is in contrast to FLT, which is retained by thymidine kinase 1 (TK1) the cytosolic enzyme associated with normal DNA synthesis. We are now testing the hypothesis that imaging cellular stress with 18F-FMAU may provide an early measure of cancer treatment response. Furthermore, FMAU may be simpler to use than agents being developed to image apoptosis, since the time course of stress may be more predictable than changes in apoptosis, which are often short term. These approaches will need to be validated against more conventional measures of response and biopsies based measurements of cell proliferation and TK activity. We are also studying labeled drugs to image their in vivo pharmacokinetics and pharmacodynamics. FAU {1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-uracil} is a chemotherapeutic agentwhich is in phase I testing. We conducted the first-in human phase 0 study of 18F-FAU to determine its suitability for imaging and to determine its potential as an antineoplastic agent. A phase I study using unlabeled FAU has started at Karmanos Cancer Institute and uses 18F-FAU and PET to monitor pharmacodynamics in tumors.
drug development using radiolabeled thymidine analogs, liposomes, and other drugs using PET
imaging cellular proliferation and stress in vivo
testing response to drug therapy for cancer
Research Description
Drug Discovery and Development
The ultimate goal of our research is to understand the response of cancer to therapy using measurements of DNA synthetic pathways as imaged by positron emission tomography (PET). Ongoing studies have refined the techniques needed to obtain PET images with radiolabeled thymidine analogs, which are trapped in the DNA synthetic pathway. Studies that began in tissue culture and mice have now progressed to clinical trials. We have addressed a number of the problems associated with interpreting the PET images including the contributions to thymidine metabolism of intracellular pools, reutilization, and degradation. The most promising compound we have used to date is 18F-FLT (3'-deoxy-3'- fluorothymidine), which is an antiviral compound like AZT. It is trapped intracellularly after phosphorylation by thymidine kinase (TK) in a manner similar to the trapping of glucose analogs (FDG) after phosphorylation by hexokinase. This compound is stable to degradation and undergoes little metabolism, aside from glucuronidation. Studies in dogs and patients indicate that it readily visualizes proliferating organs such as the bone marrow, as well as tumors. Another analog, 18F-FMAU {1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-thymine} is being studied in cell culture, animals and humans. Our in human studies found that FMAU was readily retained in tumors, but not in normally prolferating bone marrow. FMAU is retained by the action of thymidine kinase 2 (TK2), a mitochondrial enzyme. We have found that increased retention reflects cellular stress. This is in contrast to FLT, which is retained by thymidine kinase 1 (TK1) the cytosolic enzyme associated with normal DNA synthesis. We are now testing the hypothesis that imaging cellular stress with 18F-FMAU may provide an early measure of cancer treatment response. Furthermore, FMAU may be simpler to use than agents being developed to image apoptosis, since the time course of stress may be more predictable than changes in apoptosis, which are often short term. These approaches will need to be validated against more conventional measures of response and biopsies based measurements of cell proliferation and TK activity. We are also studying labeled drugs to image their in vivo pharmacokinetics and pharmacodynamics. FAU {1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-uracil} is a chemotherapeutic agentwhich is in phase I testing. We conducted the first-in human phase 0 study of 18F-FAU to determine its suitability for imaging and to determine its potential as an antineoplastic agent. A phase I study using unlabeled FAU has started at Karmanos Cancer Institute and uses 18F-FAU and PET to monitor pharmacodynamics in tumors.
研究兴趣
论文共 452 篇作者统计合作学者相似作者
按年份排序按引用量排序主题筛选期刊级别筛选合作者筛选合作机构筛选
时间
引用量
主题
期刊级别
合作者
合作机构
Otto Muzik,Anthony F. Shields,Geoffrey R. Barger,Huailei Jiang, Parthasarathi Chamiraju,Csaba Juhász
Molecular Imaging and Biologyno. 1 (2024): 29-35
Claire Gallois,Qian Shi,Levi D Pederson,Thierry André,Timothy J Iveson,Alberto F Sobrero,Steven Alberts,Aimery de Gramont, Jeffrey A Meyerhardt,Thomas George, Hans-Joachim E Schmoll,Ioannis Souglakos,
Journal of clinical oncology : official journal of the American Society of Clinical Oncologypp.JCO2301326-JCO2301326, (2024)
Maxim Yankelevich,Archana Thakur,Shakeel Modak,Roland Chu,Jeffrey Taub, Alissa Martin,Dana Schalk, Amy Schienshang, Sarah Whitaker, Katie Rea,Daniel W Lee,Qin Liu,
Journal for immunotherapy of cancerno. 3 (2024)
JOURNAL FOR IMMUNOTHERAPY OF CANCERno. 1 (2024)
Husain Yar Khan,Amro Aboukameel,Md Hafiz Uddin,Sahar F. Bannoura, Khaled Keffri, Medha Jasti, Rachael Virga, Sarah Motorwala, Khalil Choucair, Tarik Hadid,Mohammad Najeeb Al-Hallak,Eliza Beal,
Cancer Researchno. 6_Supplement (2024): 4574-4574
Husain Y. Khan,Amro Aboukameel,Md Hafiz Uddin,Mohammad Najeeb Al-Hallak,Eliza W. Beal,Ibrahim Azar,Erkan Baloglu,Rafic Beydoun,Ammar Sukari,Misako Nagasaka, Amr Mohamed,Ahmed Kaseb,
CANCER RESEARCHno. 2 (2024)
Claire Gallois,Qian Shi,Levi D. Pederson,Thierry André,Timothy J. Iveson,Alberto F. Sobrero,Steven Alberts,Aimery de Gramont, Jeffrey A. Meyerhardt,Thomas George, Hans-Joachim E. Schmoll,Ioannis Souglakos,
Journal of Clinical Oncology (2024)
Jim Abraham,Valeriy Domenyuk, Maria Perdigones Borderias, Takayuki Yoshino,Elisabeth I. Heath,Emil Lou,Stephen Liu,John Marshall,Wafik S. El-Deiry,Anthony Shields, Martin Dietrich,Yoshiaki Nakamura,
Cancer Researchno. 6_Supplement (2024): 2300-2300
Hadas Reuveni,Mohammed Najeeb Al-Hallak, Sarah Motorwala,Eliza Beal,Steve Kim,Rafic Beydoun, Gergory Dyson, Bassel El-Rayes,Herbert Chen,Philip A. Philip,Anthony F. Shields, Boris Pasche,
Cancer Researchno. 6_Supplement (2024): 1939-1939
Molecular Therapy: Oncologyno. 1 (2024): 200786-200786
加载更多
作者统计
合作学者
合作机构
D-Core
- 合作者
- 学生
- 导师
数据免责声明
页面数据均来自互联网公开来源、合作出版商和通过AI技术自动分析结果,我们不对页面数据的有效性、准确性、正确性、可靠性、完整性和及时性做出任何承诺和保证。若有疑问,可以通过电子邮件方式联系我们:report@aminer.cn