DNA Uptake of ¹³¹I-Iododeoxyuridine

TO THE EDITOR:

It was with great interest that we read the publication by Dr. Kwan-Hwa Chi et al. (1). They reported on the interesting approach of using antisense thymidylate synthase (TS) plasmids to improve the DNA uptake of ¹³¹I-iododeoxyuridine (IdUrd). However, as interesting as this approach is, the presented data do not seem to fully support the authors’ claim of improved uptake and improved antitumor activity for ¹³¹I-IdUrd in the presence of these antisense TS plasmids. Moreover, we bring to the editor’s attention a potentially dangerous procedure described and used by the authors to prepare the title reagent, ¹³¹I-IdUrd.

The uncertainty in the in vitro uptake and toxicity studies and in the in vivo tumor growth evaluation arises from the method of ¹³¹I-IdUrd preparation. For each 3.7 MBq of ¹³¹I, the authors used 0.05 mg of the stannylated precursor in the synthesis of ¹³¹I-IdUrd. The authors used no methods to purify ¹³¹I-IdUrd of unreacted stannylated precursor and its byproducts. The removal in vacuo of the volatile components from the reaction mixture does not purge this mixture of stannylated derivatives. Incidentally, evaporation of unreacted ¹³¹I with the aid of a vacuum is a dangerous practice and unless conducted with proper and efficient filters can result in air contamination and thyroid uptake of airborne ¹³¹I.

The authors claimed that in vitro uptake of, and in vivo tumor response to, ¹³¹I-IdUrd were significantly improved with antisense TS plasmids. This may be an erroneous conclusion for the simple reason that each tumor was treated with 0.15 mg of the stannylated precursor and its byproducts, in addition to 11.1 MBq of ¹³¹I-IdUrd. We have shown (unpublished data, 2003) that trialkylstannylated deoxyuridine is quite cytotoxic, even at concentrations 15–150 times lower than those in mixtures used by Chi et al. to treat mice. In the absence of the proper control—that is, tumors treated with stannylated precursors with or without antisense TS plasmids—a claim that tumor response to ¹³¹I-IdUrd was improved is unsubstantiated. It is just as likely that tumors responded to a continuous supply of cytotoxic trialkylated tin derivatives. Similarly, the increased in vitro uptake of ¹³¹IdUrd (Fig. 3 of Chi et al. (1)) could very well have been in response to repair of the DNA damage caused by the stannylated derivatives.

The decoupling of these two effects—radiotoxicity of ¹³¹I-IdUrd and cytotoxicity of stannylated precursors/byproducts—is impossible in the experimental design presented in this paper.

The synthesis of any no-carrier-added radiopharmaceutical is exacting because molar quantities of the radiolabeled materials are often >15,000 less, as is the case here, than the molar quantities of nonradioactive precursors and byproducts. When these precursors or byproducts are cytotoxic in their own right, the information obtained with uncharacterized radioactive mixtures cannot be taken at its face value regardless of how exciting these results may seem.