6-Thioguanine actions

A number of thiopurines (thioguanine, 6-mercaptopurine, 6-(methylthio) purine, azathioprine (6[( l-methyl-4-nitro-5-imidazolyl)thio] purine) [12],and other derivatives of 6-mercaptopurine [377]) have all been used to successfully prolong homografts, and azathioprine (Imuran) appears to be superior in its action [268]. 

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. 

In Fig. 1 various targets of some important cytostatic agents are depicted. Their main mechanisms of action can be briefly summarized as follows. Pentostatin blocks purine nucleotides by inhibiting adenosine deaminase. 6-Mercaptopurine and 6-thioguanine inhibit purine ring biosynthesis and they inhibit nucleotide interconversions. Methotrexate by inhibiting dihydrofolate reduction blocks thymidine monophosphate and purine synthesis. 5-Fluorouracil also blocks thymidine monophosphate synthesis. Dactinomycin, daunorubicin, doxorubicin and mitoxantrone intercalate with DNA and inhibit RNA synthesis. L-asparaginase deaminates... 

Thioguanine is a purine analogue structurally related to 6-mercaptopurine and azathioprine. Thioguanine interferes with several enzymes required for de novo purine synthesis, and its metabolites are incorporated into DNA and RNA, further impeding nucleic acid synthesis. The mechanism of action of thioguanine in psoriasis is not clearly understood it has been hypothesized to affect the proliferation and trafficking of lymphocytes as well as the proliferation of keratinocytes. 

Swann PF, Waters TR, Moulton DC et al. Role of postreplieative DNA mismateh repair in the cytotoxic action of thioguanine. Science 1996 273 1109-1111. 

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. 

Thiopurines are metabolized by thiopurine methyltransferase, whose activity is controlled by a common genetic polymorphism in the short arm of chromosome 6. Patients with low or intermediate activity who take azathioprine or 6-mercaptopurine are at risk of myelosup-pression caused by excess accumulation of the active thiopurine metabolite 6-thioguanine nucleotide. Benzoic acid derivatives, such as mesalazine and its precursors, and prodrugs (sulfasalazine, olsalazine, and balsalazide) inhibit thiopurine methyltransferase activity in vitro. This action could explain the increase in whole blood concentrations of 6-thioguanine nucleotide, leading to leukopenia. 

Thioguanine is similar to 6-mercaptopurine in its action. The most active form is 6-thio-GMP, which inhibits guanylate kinase and, at higher concentrations, IMP dehydrogenase. Thio-IMP and thio-GMP also inhibit PRPP amidotransferase. 

Two of the more important purine analogs in use clinically are 6-mercaptopurine and 6-thioguanine. These purine antagonists and glutamine antagonists such as azaserine (Table 4-6) are major antagonists in the biosynthesis of purine bases. Before understanding the mechanism of their action, it is necessary to look at the biosynthesis of inosinic acid, the purine ribonucleotide that is the precursor to both purine bases found in DNA and RNA... 

Thioguanine has multiple metabolic effects. Its tumor inhibitory properties may be due to one or more of its effects on feedback inhibition of de novo purine synthesis inhibition of purine nucleotide interconversions or incorporation into DNA and RNA. The net conseqnence of its actions is a sequential blockade of the synthesis and utilization of the purine nucleotides. 

The antimetabolites are structurally similar to endogenous compounds and are antagonists of folic acid (methotrexate), purines (mercaptopurine, thioguanine), or pyrimidines (fluorouracil, cy-tarabine). Antimetabolites are CCS drugs acting primarily in the S phase of the cell cycle. Their sites of action on DNA synthetic pathways are shown in Figure 55-3. In addition to their cytotoxic effects on neoplastic cells, the anti metabolites also have immunosuppressant actions. Some of the uses of the antimetabolites in neoplastic disease are listed in Table 55-2. 

Mechanisms of action and resistance Mercaptopurine and thioguanine are purine antimetabolites. Both drugs are activated by hypoxanthine-guanine phosphoribosyltrans-ferases (HGPRTases) to toxic nucleotides that inhibit several enzymes involved in purine... 

Although 6-thioguanine has been used for over thirty years for treatment of hunum malignancies, the precise molecular basis for its action is still not undo stood. Recent evidence has... 

A number of purine nucleotide analogues can mimic the effects of natural purine ribonucleotides on PP-ribose-P amidotransferase and thereby effect feedback inhibition of the entire pathway (69, 60). Such nucleotide analogues may be synthesized by cells from purine bases or nucleosides presented to them. A number of compounds with potent inhibitory properties, such as 6-mercaptopurine, 6-thioguanine, and 6-methylmercaptopurine ribonucleoside, inhibit purine biosynthesis de novo in this way, although it is not known whether this action is responsible for the growth inhibition. 

It is known that the toxic action of 6-mercaptopurine can be prevented by injection of adenylic acid or by a number of related substances (214)-6-Mercaptopurine has been found to inhibit DPN synthesis in the liver of mice injected with nicotinamide (199). This inhibition can be antagonized by an administration of adenylic add. Similar results have been obtained with another purine antagonist, thioguanine. Both 6-mercaptopurine and thioguanine not only decrease the amount of DPN synthesis but also interfere with the return of the DPN to its normal value at the end of the 24-hr period. The difference at 24 hr for 6-mercaptopurine was found to be as great as fivefold. The effect of the drug on the return to normal levels is not reversed by the introduction of adenylic acid. 

---