Radioiodinated agents for imaging multidrug resistant tumors.
Diagnostic agents enabling characterization of multidrug resistance (MDR) in tumors can aid in the selection of chemotherapy regimens. We report here synthesis and evaluation of radiopharmaceuticals based on the second-generation MDR-reversing drug MS-209. 5-[3-{4-(2-Phenyl-2-(4'-[(125)I]iodo-phenyl)acetyl)piperazin-1-yl}-2-hydroxypropoxy]quino-line (17) was prepared from the 4'-tributylstannyl precursor (16) in >95% radiochemical yield. (16) was synthesized in a six-step process with the overall yield of 25%. In vitro studies were conducted in MES-SA (drug-sensitive) and MES-SA/Dx5 (MDR) human uterine sarcoma cell lines. In vivo studies were performed in athymic mice bearing MES-SA and MES-SA/Dx5 xenografts. The uptake of (17) is higher in MES-SA than MES-SA/Dx5 cells. The uptake and efflux of (17) depend on temperature and concentration, and indicate active transport mechanism(s). Incubation of drug sensitive MES-SA cells with verapamil or (15), a nonradioactive analog of (17), alters the cellular retention of radioactivity only marginally. However, MES-SA/Dx5 cells retain approximately 12% more of (17) when incubated with 10 muM verapamil. The addition of (15) or high concentrations of (17) also increase the uptake of (17) in MES-SA/Dx5 up to 200%, depending on the concentration and temperature. The dependence of (17) uptake on the MDR status is also evident in the ex vivo binding studies. In vivo tests in mice xenografted simultaneously with both tumor cell lines indicate distinct pharmacokinetics for each tumor. The absorption half-life in MES-SA/Dx5 xenograft is approximately 10x shorter and the mean residence time approximately 50% shorter compared to MES-SA xenograft in the same mouse. Radioiodinated derivatives of MS-209 appear to be good indicators of multidrug resistance.
Kortylewicz
Zbigniew P
ZP
University of Nebraska Medical Center, Department of Radiation Oncology, J. Bruce Henriksen Laboratories for Cancer Research, Omaha, Nebraska 68198-6850, USA.
Augustine
Ann M
AM
Nearman
Jessica
J
McGarry
Jonathon
J
Baranowska-Kortylewicz
Janina
J
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007457:Iodine Radioisotopes / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D011877:Radionuclide Imaging / Q000379:methods*; D019275:Radiopharmaceuticals / Q000032:analysis* / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics*; D013696:Temperature; D013997:Time Factors; D014018:Tissue Distribution; D014700:Verapamil / Q000494:pharmacology
D000970:Antineoplastic Agents; D007457:Iodine Radioisotopes; D011804:Quinolines; D019275:Radiopharmaceuticals; C087719:dofequidar; D014700:Verapamil