2-thioguanine

Therapeutic Function Cancer chemotherapy Chemical Name 2-aminopurine-6-thiol Common Name — 

A mixture of 2.7 grams of finely divided guanine, 10 grams of pulverized phosphorus pentasulfide, 10 ml of pyridine and 100 ml of tetralin was heated at 200°C with mechani- 

Therapeutic Function Cancer chemotherapy Chemicai Name 2-amlnopurlne-6-thiol Common Name - 

ACS Symposium Series American Chemical Society Washington, DC, 1980. 

EFFECT OF PRETREATMENT WITH BENZOPYRENE UPON THE TRANSFORMATION OF SYRIAN HAMSTER EMBRYO CELLS BY NICKEL COMPOUNDS 

Treatment Conditions 5,000 Cells Plated 10,000 Cells Plated No. of Transformed Foci per Plate  

EFFECT OF BENZOPYRENE PRETREATMENT ON PLATING EFFICIENCY IN CULTURES SUBSEQUENTLY TREATED WITH Ni3S2 

Third passage log phase cultures of Syrian hamster fetal cells were treated as described in the table. Cultures treated with benzopyrene and Ni3S2 were exposed to benzopyrene for 24 h prior to treatment with the metal. Cultures were treated with the metal compounds three times using a two-day exposure for each treatment. Cells were then removed from the plate by trypsini-zation and the number of cells present in each plate was determined with a hemocytometer. Five thousand or ten thousand cells were replated to form colonies into 100 mm diameter plates and the number of surviving colonies in each plate was counted. Each number shown in the table is the mean of four tissue culture plates. 

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The current induction therapy for acute myelogenous leukemia (AML) usually consists of a combination of cytara-bine and daunorubicin, with the frequent addition of a steroid and/or an antimetabolite such as 6-thioguanine. The risk of infection is so high during this period that patients receive antibiotic and fungal prophylaxis. 

Rappaport HP (1988) The 6-thioguanine/5-methyl-2-pyrimidinone base pair. Nucl Acids Res 16(15) 7253-7267... 

Chen ZS, Lee K, Kruh GD. Transport of cyclic nucleotides and estradiol 17-beta-D-glucuronide by multidrug resistance protein 4 Resistance to 6-mercap-topurine and 6-thioguanine. J Biol Chem 2001 276(36) 33747—33754. 

At cellular level, 6-MP is transformed in a number of active and inactive metabolites, and in the bone marrow, the balance between activation and inactivation of 6-MP is the main determinant of its antiproliferative effect. Similar to other antimetabolites, 6-MP is a prodrug lacking any cytotoxic activity and needs to be activated [3] (Figure 14.1). The first step is 6-MP transformation into 6-thioinosine monophosphate (6-TIMP), which is subsequently converted to 6-thioguanine tri-... 

Ling YH, Chan JY, Beattie KL et al. Consequences of 6-thioguanine incorporation into DNA on polymerase, ligase, and endonuclease reactions. Mol Pharmacol 1992 42 802-807. 

McBride KL, Gilchrist GS, Smithson WA et al. Severe 6-thioguanine-induced marrow aplasia in a child with acute lymphoblastic leukemia and inhibited thiopurine methyltransferase deficiency. J Pediatr Hematol Oncol 2000 22 441-445. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980 32 651-662. 

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine dmgs, such as 6-mercaptopurine (6-MP), 6-thioguanine and azathioprine, to inactive metabolites [29-32]. Thiopurines form part of the routine treatment for patients with acute lymphoblastic leukemia, rheumatoid arthritis, and autoimmune diseases such as SLE and Crohn s disease, and are used as an immunosuppressant following organ transplantation. 

Thioguanine (6-TG) -purine analogue antimetabolite cell cycle dependent -bone marrow suppression -nausea and vomiting -mucocutaneous effects (mucositis, stomatitis) -rash -hepatotoxicity -hyperuricemia... 

Garner RC, Campbell J. 1985. Tests for the induction of mutations to ouabain or 6-thioguanine resistance in mouse lymphoma L5178Y cells. In Ashby J, de Serres FJ, et al., eds. Progress in mutation research. Vol. 5. Evaluation of short-terms tests for carcinogens. Amsterdam, The Netherlands Elsevier Science Publishers, 525-529. 

The answer is a. (Hardman, p 1302.) Cyclophosphamide, an alkylating agent, reacts with purine and pyrimidine bases of DNA to form bridges and dimers. These products interfere with DNA replication. 5-FU, methotrexate, and 6-thioguanine are anti metabolites, and the steroid prednisone has some tumor-suppressive effects. 

Thioguanine is a purine analog that has been used as an alternative treatment for psoriasis when conventional therapies have failed. The typical dose is 80 mg twice weekly, increased by 20 mg every 2 to 4 weeks the maximum dose is 160 mg three times a week. Adverse effects include bone marrow suppression, GI complications (e.g., nausea, diarrhea), and elevation of liver fimction tests. 6-Thioguanine may be less hepatotoxic and therefore more useful than methotrexate in hepatically compromised patients with severe psoriasis. 

Susceptibility to excessive myelosuppression from 6-mercaptopurine, 6-thioguanine, azathioprine in treatment of acute lymphocytic leukemia (thiopurine methyltransferase)... 

The cell suspension is diluted in complete medium and 2 x 105 cells added per petri dish (10 petri dishes per treatment). 6-Thioguanine is added to the medium at a final concentration of lOpgml-1. 

Fig. 14.2 Scheme of thiopurine drug metabolism. HPRT, hypoxanthine phosphoribosyl transferase 6-MMP, 6-methylmercaptopurine 6-TGN, 6-thioguanine nucleotides 6-TIMP, 6-thiosine monophosphate TPMT, thiopurine methyltransferase XO, xanthine oxidase... 

The ribonucleotides of 6-mercaptopurine, 6-thioguanine, 6-chloropurine, and purine have been prepared chemically for biochemical investigations [138-141 ]. 

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. 

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