Guanine Thioguanine

The answer is c. (Katzung, p 933.) Resistance to thioguanine occurs because of an increase in alkaline phosphatase and a decrease in hypoxanthine-guanine phosphoribosyl transferase. These enzymes are responsible, respectively, for the increase in dephosphorylation of thiopurine nucleotide and the conversion of thioguanine to its active form, 6-thioinosinic acid. 

It has been suggested that thioguanine s multistep inhibition, one step of which is the inhibition of phosphoribosylpyrophosphate amidotransferase, results in a profound lowering of the intracellular concentration of guanine nucleoside phosphates and that this depletion causes a marked depression in cellular metabolism that presumably would lead to cell death [91 ]. 

Another guanine analogue, thioguanine, is also incorporated into both DNA and RNA of mammalian cells [198], and a correlation between its antitumour activity and the extent of its incorporation into DNA has been observed [339,340], although some investigators feel that the metabolic effects of thioguanylic acid may be more universally important [13, 91, 341]. The incorporation of a- and... 

In the body, thiognanine is converted into an active form, 6-thioguanin-5-phosphate. The main mechanism of its action consists of including its triphosphate form into DNA, replacing the guanine nncleotide, and inhibiting DNA synthesis. 

Thioguanine (6-TG) also inhibits several enzymes in the de novo purine nucleotide biosynthetic pathway. Various metabolic lesions result, including inhibition of purine nucleotide interconversion decrease in intracellular levels of guanine nucleotides, which leads to inhibition of glycoprotein synthesis interference with the formation of DNA and RNA and incorporation of thiopurine nucleotides into both DNA and RNA. 6-TG has a synergistic action when used together with cytarabine in the treatment of adult acute leukemia. 

Since guanine aminohydrolase catalyzes the deamination of thioguanine and 8-azaguanine thereby destroying their anti-neoplastic effects, Baker and his colleagues have prepared a series of active site directed irreversible inhibitors to block the enzyme in tumor tissue (193). The most effective inhibitor, 9-(4-methoxy phenyl)guanine, effected a 50 inhibition at 0.38 nM in the presence of 13.3 juM substrate (194). 

Mercaptopurine (6MP) and 6-thioguanine (6TG) are analogs of the purines hypoxanthine and guanine, which must be activated by nucleotide formation, according to the following scheme ... 

Mutations to loss of activity of this enzyme cause resistance to the guanine analogues 8-azaguanine and 6-thioguanine. Thus, wild-type HPRT " cells can be selected against by incorporation of one of these analogues. 

THIOGUANINE An analogue of the purine base guanine, which is a normal component of DNA and RNA selection for resistance to the toxic effects of 6-thioguanine is the basis of several mutation-detection systems. 

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