4-Fluorobenzylamine and phenylalanine methyl ester conjugates of 2-nitroimidazole: evaluation as hypoxic cell radiosensitizers.
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| Abstract |
We have synthesized two 2-nitroimidazole derivatives and evaluated their hypoxic radiosensitization properties. The first, a 4-fluorobenzylamine conjugate of 2-nitroimidazole (PK-110), was designed so that it could also be labeled with the F-18 and used for positron emission tomographic imaging of hypoxia. The second, the L-phenylalanine methyl ester conjugate of 2-nitroimidazole (PK-130), was designed in an attempt to exploit amino acid transport channels to enhance drug transport into the tumor. The effects of these drugs (and SR-2508, for comparison) in vitro on the aerobic and hypoxic radiosensitivity of Chinese hamster V79 cells were evaluated using clonogenic assays. PK-130 and PK-110 at 0.1 and 1.0 mM were more efficient hypoxic cell radiosensitizers than obtained with 1.0 mM SR-2508. Marginal aerobic radiosensitization was observed for 1.0 mM treatment with PK-130 and PK-110, however, no aerobic radiosensitization was observed at 0.1 mM. Glutathione (GSH) depletion (less than 5% of control levels) by L-buthionine sulfoximine (BSO) further enhanced the SER for both PK-130 and PK-110 at 0.1 mM to 3.2 +/- 0.63 and 2.4 +/- 0.16, respectively. The results of this study encourage the in vivo tumor radiosensitization evaluation of PK-130 and PK-110.
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| Authors | P K Garg, S Garg, W G Degraff, M R Zalutsky, J B Mitchell |
| Journal | International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 22 Issue 3 Pg. 593-6 ( 1992) ISSN: 0360-3016 [Print] United States |
| PMID | 1531220 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.) |
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