Potential Use of Radiolabeled Glucuronide Prodrugs with Auger and/or Alpha Emitters in Combined Chemo- and Radio-Therapy of Cancer

Abstract

Nowadays, the scientists from different disciplines have focused their attentions to new anticancer drug design for cancer chemotherapy. An effective anticancer drug should ensure the selective drug incorporation into the targeted tumor cells without principally incorporation into the normal cells. So, the targeted tumor cells can selectively be damaged by the cytotoxic effectiveness of the drug. The basic principles of drug design have involved "prodrug" concept, which means a chemical agent which is not itself active as an anticancer drug, but it can be transformed to an active form after its administration. Prodrugs can finally be activated onto the tumor cells by some kind of enzymes. In this context, the activation of glucuronide prodrugs by b-glucuronidase have a large potential applications in cancer chemotherapy. On the other hand, combined chemo- and radio-therapy of cancer (CCRTC) concept aims to combine the cytotoxicity of an aglycone with the radiotoxicity of an appropriate radionuclide on the same prodrug. So, the cytotoxic and radiotoxic effectiveness' will be able to be concentrated into the same tumor cell to increase obviously its damage. For experimental realization of this concept an effective anticancer prodrug should be radiolabeled with a radionuclide having high level of radiotoxic effectiveness such as Auger and/or alpha-emitter radionuclides. Iodine-125 and astatine-211 are very interesting radionuclides as being effective Auger and/or alpha-emitters. Briefly, the glucuronide prodrugs radiolabeled with iodine-125 or astatine-211 promise to be designed very effective anticancer agents in the future applications of cancer chemotherapy.

Characterization of Arabidopsis AtUGT85A and AtGUS gene families and their expression in rapidly dividing tissues

“…Though its normal substrates are not well characterized, it has been implicated in functions ranging from sperm cytoskeleton structure [43] to regulation of thyroid hormone levels in cardiac fibroblasts [44]. Its key role in metabolism has made it a prime target for genetic therapies in humans [45,46].…”

Metabolic Comparison of Radiolabeled Bleomycin and Bleomycin-Glucuronide Labeled with 99mTc

“…7,8 Indeed, several glucuronide prodrugs have already been selectively activated by b-glucuronidase, either present in high concentration in necrotic tumor areas 9,10 or previously targeted to the tumor sites antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) 11 and consequently demonstrated superior efficacy in vivo compared with standard chemotherapy. 12 These results were attributed to the increased drug deposition and retention in the tumor connected with reduced anticancer agent concentration in normal tissues, considerably lowering the destruction of normal cells. Therefore, glucuronide prodrugs are activated by human enzyme b-glucuronidase in ADEPT and GDEPT.…”

Tumor-specific activation of prodrugs: is there a role for nuclear medicine?

“…For such specific strategies, knowledge of the expression levels and the distribution of the PD-converting enzyme is vital. Therefore, noninvasive imaging techniques, such as PET, can be attractive tools to evaluate new enzyme-PD combinations and to optimize treatment strategies [3][4][5].…”

“…For imaging purposes, glucuronide-based tracers could be developed with similar structures as the PD. So far, only a few glucuronide PDs have been radiolabeled with 125 I and 211 At to enhance the efficacy of these PDs by adding radiotoxicity of an appropriate radionuclide in the same PD [5,18]. When other isotopes are applied, these labeled compounds might be suitable tracers for imaging.…”