Current Pharmaceutical Design - Volume 6, Issue 11, 2000

A variety of radiopharmaceuticals have been introduced for the internal therapy of malignant and inflammatory lesions in nuclear medicine. In order to destroy the disseased tissues radionuclides with high linear energy transfer (LET) such as beta, alpha, Auger or low energy conversion electron emitters are needed. The range of beta particles is in mms so they are effective for large tumors. The range of alpha particles is short, only a few cell diameters. Thus, they are effective in treating circulating malignant cells and micrometastases. The range of Auger and conversion electrons is than0.1 micro m. They are very effective in cell killing when they are carried across cell membrane into the nucleus to damage DNA. Appropriate ions, molecules and particles are labelled with such radionuclides and used as radiopharmaceuticals in many different applications. For an effective dose to be delivered high target to non target ratios must be attained. Monoclonal antibodies to specific antigens expressed on tumor cells have been developed to increase the uptake by malignant tissues by specific accumulation. Radiolabelled peptides such as somatostatin, small molecules such as metaiodo-benzylguanidine (MIBG) and many different nano-and micro-particles have been investigated. The effectiveness of therapy can be increased by direct locoregional administration of the radiopharmaceutical. This way the radiation effects are confined locally and the normal tissues are spared from radiation effects.

Development of peptides and amino acids labeled with single photon gamma emitters has promoted a large number of investigations in nuclear medicine especially for tumor imaging. Radiolabeled peptides have several advantages over antibodies mainly related to immunogenicity and size. Tumor localization and total body clearance of peptides are more rapid compared to antibodies. Recently, several somatostatin analogues labeled with Tc-99m have been studied by several different investigators. In-111 labeled lanreotide (Mauritus) was reported to be highly successful in localization of neuroendocrine tumors. A synthetic amino acid, alpha methyl tyrosine labeled with I-123 was shown to be transported to tumors by a carrier mediated system. Development of a glucose analog labeled with a single photon emitting radionuclide and meeting the structural requirements for hexokinase reaction and phosphorylation have not yet been possible. However, it has been possible to synthesize chemically stable single photon glucose analogues interacting with glut(s), glucose transporters.

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.

In vivo imaging techniques like positron emission tomography (PET) and single photon emission computed tomography (SPECT) offer the possibility to monitor human central nicotinic acetylcholine receptors (nAChRs) in a variety of central nervous system disorders. In the past, the only available PET radiotracer for imaging nAChRs in the human brain, ( 11 C)-(-)-nicotine, suffered from a spectrum of not suitable properties for in vivo imaging. Current efforts are focused on the development of new, highly specific and highly selective radioligands based on different structural classes (e.g. nicotine, epibatidine, 3-pyridyl ether analogues) for central nAChRs. The most promising compounds are halogenated 3-pyridyl ether compounds for imaging a4beta2 nAChRs. But there is still a lack for radiotracers for other subtypes of nicotinic acetylcholine receptors being a promising area of interest.

Many radiopharmaceuticals have been introduced for the scintigraphic demonstration of infectious and inflammatory lesions and some of them are currently in clinical use. They can be classified into two major categories according to their specificity. Specific radiopharmaceuticals include in vitro labeled leukocytes, radio-labelled monoclonal antibodies, and receptor specific small proteins and peptides. Nonspecific radiopharmaceuticals include radiolabelled nanocolloids, liposomes, macromolecules such as human immunoglobulin, dextran and human serum albumin, various small molecules and ions. In this review article radiopharmaceuticals in their respective groups are discussed as to the efficacy, and other parameters such as the physical characteristics of the radionuclides used, radiochemistry involved, availability, cost and biodistribution, emphasizing recent developments.

The influence of drugs on the labeling of red blood cells and plasma proteins with 99mTc has been reported. Any drug, which alters the labeling of the tracer, could be expected to modify the disposition of the radiopharmaceuticals. Red blood cells (RBC) labeled with technetium-99m (99mTc) are used for several evalua-tions in nuclear medicine. We have evaluated the effect of Thuya occidentalis, Peumus boldus and Nicotiana tabacum (tobacco) extracts on the labeling of RBC and plasma and cellular proteins with 99mTc. Blood was incubated with the drugs. Stannous chloride (SnCl2 ) solutions and 99mTc were added. Plasma (P) and blood cells (BC) were separated. The percentage of radioactivity (percentATI) bound to P and BC was determined. The percentATI on the plasma and cellular proteins was also evaluated by precipitation of P and BC samples with trichloroacetic acid (TCA) and isolation of soluble (SF) and insoluble (IF) fractions. The analysis of the results shows that there is a decrease in percentATI (from 97.64 to 75.89 percent) in BC with Thuya occidentalis extract. The labeling of RBC and plasma proteins can be decreased in presence of tobacco. This can be due either a direct or indirect effect (reactive oxygen species) of tobacco. The analysis of radioactivity in samples of P and BC isolated from samples of whole blood treated with Peumus boldus showed a rapid uptake of the radioactivity by blood cells in the presence of the Peumus boldus, whereas there was a slight decrease in the amount of 99mTc radioactivity in the TCA-insoluble fraction of plasma. This study shows that extracts of some medicinal plants can affect the radiolabeling of red blood cells with 99mTc using an in vitro technique.