Clinical trials of radiotherapy to control drug delivery were initiated in 1999 at Vanderbilt University. The initial studies exploited the findings that platelets are activated in tumor blood vessels after high-dose irradiation as used in radiosurgery and high-dose-rate brachytherapy. Platelets labeled with 111In showed binding in tumor blood vessels. However, the platelet labeling process caused platelets to also accumulate in the spleen. That clinical trial was closed, and subsequent clinical trials targeted protein activation in irradiated tumor blood vessels. Preclinical studies showed that peptide libraries that bind within irradiated tumor blood vessels contained the peptide sequence Arg-Gln-Asp (RGD). RGD binds to integrin receptors (e.g., receptors for fibrinogen, fibronectin, and vitronectin). We found that the fibrinogen receptor (GPIIb/IIIa, α2bβ3 is activated within irradiated tumor blood vessels. RGD peptidemimetics currently in clinical trials include GPIIb/IIIa antagonists and the platelet-imaging agent biapcitide. Biapcitide is an RGD mimetic that is labeled with 99Tc to allow gamma camera imaging of the biodistribution of the GPIIb/IIIa receptor in neoplasms of patients treated with radiosurgery. This study has shown that the schedule of administration of the RGD mimetic is crucial. The peptide mimetic must be administered immediately before irradiation, whereas the natural ligands to the receptor compete for biapcitide binding if biapcitide is administered after irradiation. The authors currently are conducting a dose deescalation study to determine the threshold dosage required for RGD mimetic binding to radiation activated receptor. Radiation-guided clinical trials have been initiated by use of high-dose-rate brachytherapy. In a separate trial, the pharmacokinetics of radiation-inducible gene therapy are being investigated. In this trial, the radiation-activated promoter Egr-1 regulates expression of the tumor necrosis factor α gene, which is administered by use of the attenuated adenovirus vector. The Ad.Egr-TNF (ADGV) gene is administered by intratumoral injection of vector followed by irradiation in patients with soft-tissue sarcomas. This review highlights recent findings in these phase I pharmacokinetic studies of radiation-controlled drug delivery systems.
|Number of pages
|American Journal of Clinical Oncology: Cancer Clinical Trials
|Published - 2001