Person:

Adelstein, Stanley

We are developing a noninvasive approach for targeting imaging and therapeutic radionuclides to prostate cancer. Our method, Enzyme-Mediated Cancer Imaging and Therapy (EMCIT), aims to use enzyme-dependent, site-specific, in vivo precipitation of a radioactive molecule within the extracellular space of solid tumors. Advanced methods for data mining of the literature, protein databases, and knowledge bases (IT.Omics LSGraph and Ingenuity Systems) identified prostatic acid phosphatase (PAP) as an enzyme overexpressed in prostate cancer and secreted in the extracellular space. Using AutoDock 3.0 software, the prodrug ammonium 2-(2'-phosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone (IQ(2-P)) was docked in silico into the X-ray structure of PAP. The data indicate that IQ(2-P) docked into the PAP active site with a calculated inhibition constant (K-i) more favorable than that of the PAP inhibitor alpha-benzylaminobenzylphosphonic acid. When (125)IQ(2-P), the radioiodinated form of the water-soluble prodrug, was incubated with PAP, rapid hydrolysis of the compound was observed as exemplified by formation of the water-insoluble 2-(2'-hydroxyphenyl)-6-[I-125] iodo-4-(3H)-quinazolinone ((125)IQ(2-OH))- Similarly, the incubation of IQ(2-P) with human LNCaP, PC-3, and 22110 prostate tumor cells resulted in the formation of large fluorescent IQ(2-OH) crystals. No hydrolysis was seen in the presence of normal human cells. Autoradiography of tumor cells incubated with (125)IQ(2-P) showed accumulation of radioactive grains ((125)IQ(2-OH)) around the cells. We anticipate that the EMCIT approach will enable the active in vivo entrapment of radioimaging and radio-therapeutic compounds within the extracellular spaces of primary prostate tumors and their metastases.

Auger-electron emitters represent an attractive alternative to beta-particle emitters for cancer therapy if they can be placed intracellularly, especially in close proximity to (or within) nuclear DNA. Based on investigations in animal tumor models, including those for ovarian cancer, bladder cancer, and brain and spinal cord tumors, in which the thymidine analog 5-radioiodo-2'-deoxyuridine (*IUdR) has been shown to be therapeutically efficacious, it is hypothesized that iodine-125 and other Auger-electron-emitting radionuclides might be valuable in the treatment of certain malignant diseases, assuming that uptake of the radiopharmaceutical by tumor cells exceeds that by normal dividing cells. Preliminary patient studies have shown that this requirement can be met partially by the locoregional administration of the radiopharmaceutical and metabolic modulation of its uptake by tumor cells. Investigators continue to seek molecules that can carry Auger-electron emitters to nuclear DNA, especially those radionuclides with higher Auger-electron yields and varying half-lives.