Differential role of thiopurine methyltransferase in the cytotoxic effects of 6-mercaptopurine and 6-thioguanine on human leukemia cells

Biomarkers Predictive of Response to Thiopurine Therapy in Inflammatory Bowel Disease

“…In addition, 6-TGN thioguanosine triphosphate (TGTP) inhibits the activity of GTPase Rac1 resulting in suppression of T cell-dependent immune response (22,24). The conversion of 6-MP into 6-methylmercaptopurine or methylthioinosine monophosphate (meTIMP) by thiopurine methyltransferase (TPMT), inhibits the enzyme phosphoribosyl pyrophosphate (PPAT) which catalyzes the first step of de novo purine synthesis (25). As a consequence, there is inhibition of DNA synthesis and cell proliferation along with cytotoxic effects (26).…”

Anti-cancerous efficacy and pharmacokinetics of 6-mercaptopurine loaded chitosan nanoparticles

“…The cells were washed with binding buffer and subjected to 0.25-0.5 mg/mL RNase treatment for 20 min at 37 • C. RNAse treated cells were washed, re-suspended in binding buffer and stained with 50 g/mL PI. Following incubation with PI for 10-15 min at RT, cells were suspended in 400 L of 1X Annexin-V binding buffer and the apoptotic/necrotic populations were analyzed by flow cytometry [3,30]. Eight to ten-week-old healthy Wistar rats of either sex weighing around 200 ± 20 g were procured from the Laboratory Animal Facility, Veterinary College, Bangalore, India.…”

“…For instance, incorporation of 6-TG induces cytotoxicity mediated via G2/M and/or S phase arrest [7,8]. However, 6-MP undergoes a complex biotransformation by XO (Xanthine oxidase) and TPMT (thiopurine S methyl transferase) which limits its bioavailability and leads to incomplete and variable bioavailability (about 16-50%) [1,9], short plasma half-life (0.5-1.5 h) [10], moderate plasma protein binding (19-30%) [11] and narrows therapeutic index which in turn results in plummeting chemotherapeutic effect and life-threatening toxicity, mainly in the form of myelosuppression [12,3].…”

“…Since its approval as an antitumour drug from Food and Drug Administration (FDA) in 1953 [2], it has been widely used in the treatment of acute lymphoblastic leukemia (ALL), rheumatological disorders, prevention of rejection following organ transplantation and inflammatory diseases [3]. 6-MP can also be used in combination with other drugs to treat diseases like systemic lupus erythematosus, non-Hodgkin-lymphoma, polycythemia vera, inflammatory diseases (Crohn's syndrome and ulcerative colitis) [4,5].…”

Preparation, Characterization and <i>In Vitro</i> Drug Release Studies of 6-mercaptopurine Thin Film

“…The thiopurines, azathioprine, 6-mercaptopurine and 6-thioguanine are effective immune-suppressants and anti-cancer agents and are prescribed increasingly to treat inflammatory diseases (Estlin, 2001). 6-mercaptopurine (6-MP) was approved as an antitumor drug by Food and Drug Administration (FDA) in 1953 (Cuin et al, 2011) and has been widely used in the treatment of Acute Lymphoblastic Leukemia and Acute Myelocytic Leukemia (Sun et al, 2013;Karim et al, 2013) and other diseases such as rheumatologic disorders, prevention of rejection following organ transplantation, systemic lupus erythematosus, non-Hodgkin-lymphoma, inflammatory diseases (Crohn's Syndrome and Ulcerative Colitis) and so on (Podsiadlo et al, 2008;Kevadiya et al, 2013). 6-MP is first metabolized to an active form methylated thioinosinic acid (MeTIMP) by hypoxanthine phosphoribosyltransferase (HPRT) within cell to inhibit de novo purine synthesis (Panetta et al, 2006) and later converted to thioguanine, which is a DNA intercalating agent.…”