Over-expression of the membrane pump P-glycoprotein (Pgp) results in multidrug resistance (MDR), a common cause of cancer treatment failure. Pgp actively removes drugs from the tumor cells. Paclitaxel is a commonly used chemotherapeutic agent, and MDR often complicates its use. The PET department at the NIH has developed an efficient radiosynthesis for [18F] paclitaxel (FPAC), which is a substrate of the Pgp pump. Because [18F] is a positron emitter, the in vivo kinetics of [18F]FPAC can be measured using positron emission tomography (PET). It is expected that, by measuring the kinetics of FPAC in tumors, the function of Pgp in vivo can be estimated. This proposal intends to obtain preliminary evidence that [18F]FPAC PET biodistribution and PET kinetic imaging parameters correspond to the measured expression of Pgp in a mouse xenograft model. Cell survival studies in two human epithelial cancer cell lines, one drug sensitive and the other drug resistant, will be used to determine the cellular response to paclitaxel. FPAC influx and efflux studies will then be performed to establish in vitro FPAC kinetics in these cell lines. These same cell lines will be used to establish a bilateral flank tumor xenograft model in nude mice. Using this mouse xenograft model, FPAC biodistribution and PET kinetic imaging studies will be performed. Immunohistochemical (IHC) staining for Pgp will be performed to quantitate the amount of Pgp protein in these tumors. Since the presence of Pgp does not imply functionality, it is necessary to determine if tumor efflux of FPAC also corresponds to MDR phenotype. This will be done by performing FPAC PET imaging and biodistribution studies in the mouse xenograft model before and after treatment with unlabeled therapeutic doses of paclitaxel. The change in xenograft size following treatment will be measured and compared to the FPAC PET imaging and biodistribution results. Because MDR is inducible, it is possible that host interaction with the xenograft or exposure to paclitaxel or FPAC may result in MDR expression that will confound the results of the above studies. Other ATP binding cassette (ABC) transporters may also be responsible for MDR. A dedicated ABC microarray-technology analysis will be performed on all tumor specimens. This microarray probes for the gene expression of 48 ABC transporters. Microarray results will be used in combination with those described above to provide preliminary evidence for FPAC's use as an in vivo marker for MDR caused by Pgp.
| Kurdziel, Karen A; Kalen, Joseph D; Hirsch, Jerry I et al. (2011) Human dosimetry and preliminary tumor distribution of 18F-fluoropaclitaxel in healthy volunteers and newly diagnosed breast cancer patients using PET/CT. J Nucl Med 52:1339-45 |
| Kurdziel, Karen A; Kiesewetter, D O (2010) PET imaging of multidrug resistance in tumors using 18F-fluoropaclitaxel. Curr Top Med Chem 10:1792-8 |
| Kurdziel, Karen A; Kalen, Joseph D; Hirsch, Jerry I et al. (2007) Imaging multidrug resistance with 4-[18F]fluoropaclitaxel. Nucl Med Biol 34:823-31 |
| Kalen, Joseph D; Hirsch, Jerry I; Kurdziel, Karen A et al. (2007) Automated synthesis of 18F analogue of paclitaxel (PAC): [18F]Paclitaxel (FPAC). Appl Radiat Isot 65:696-700 |
