Effects of thioguanine: A Synthesis of Findings from 28 Studies

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Original Abstract of the Article

Major Research Findings

Thioguanine has been investigated in various studies, showing diverse effects on cells and organisms. 10 suggests that thioguanine can effectively treat psoriasis. It works by inducing apoptosis in activated T lymphocytes, which are known to infiltrate skin tissue and contribute to the disease. However, 17 points out that thioguanine, when combined with radiotherapy or chemotherapy, can exhibit genotoxic effects on lymphocytes in breast cancer patients. Notably, radiation therapy showed greater genotoxic potential compared to thioguanine. Meanwhile, 18 highlights the cross-resistance to thioguanine and N-methyl-N-nitrosourea (MNU) in a cell line resistant to both agents. This cross-resistance is associated with the cells' ability to tolerate DNA damage. 12 reveals that increasing the dosage of thioguanine in children with lymphoblastic leukemia results in elevated thioguanine nucleotide levels in red blood cells. This suggests the need for careful dosage adjustments to maximize therapeutic effects. 21 demonstrates that asbestos fibers do not significantly increase the formation of thioguanine-resistant mutants. However, these fibers can be cytotoxic, impair cell division, and lead to abnormal cell division patterns. 8 emphasizes the differential effects of thiopurine methyltransferase (TPMT) on thioguanine and mercaptopurine. TPMT inactivates thiopurines, but in the case of thioguanine, methylation by TPMT reduces its activity. Therefore, high TPMT activity weakens thioguanine's effectiveness. In contrast, for mercaptopurine, higher TPMT activity promotes its activation, leading to increased cellular toxicity. These studies indicate that thioguanine exerts multifaceted effects on cells. Its efficacy is influenced by factors like dosage, TPMT activity, and the presence of other drugs. Therefore, careful consideration of these factors is crucial when administering thioguanine in treatment regimens.

Benefits and Risks

Benefits Summary

Thioguanine holds potential as a therapeutic agent for conditions like psoriasis and childhood leukemia. It can induce apoptosis in activated T lymphocytes, potentially leading to improvement in psoriasis symptoms. In leukemia treatment, thioguanine is often used in combination with mercaptopurine. Increasing the dosage of thioguanine may enhance its effects by increasing thioguanine nucleotide levels in red blood cells, which could suppress leukemic cell growth.

Risks Summary

Thioguanine may pose genotoxic risks to peripheral blood lymphocytes, particularly when combined with radiotherapy or chemotherapy. It can also have adverse effects on the liver, potentially leading to liver dysfunction or hepatitis. While long-term, low-dose thioguanine use appears to have minimal impact on liver health, higher doses can increase the risk of liver problems. Additionally, thioguanine can cause myelosuppression, a condition characterized by a decrease in blood cell production due to bone marrow suppression. This can result in symptoms like anemia, leukopenia, and thrombocytopenia.

Comparison Across Studies

Commonalities

Several studies consistently demonstrate that thioguanine can inhibit cell growth and induce cell death. They also acknowledge that various factors, including dosage, TPMT activity, and the presence of other drugs, significantly influence thioguanine's effects.

Differences

There are inconsistencies in the findings regarding thioguanine's effectiveness. For example, 10 suggests thioguanine's efficacy in treating psoriasis, while other studies have not shown similar results. Similarly, the genotoxic potential of thioguanine varies across studies. 17 suggests a potential genotoxic risk when used with radiotherapy or chemotherapy, while other studies have not observed such effects. These differences might be attributed to factors like the type of cells or animals studied, the dosage and administration method, and the type of drugs used in combination.

Consistency and Contradictions in Findings

Due to the various factors influencing thioguanine's effects, inconsistencies may arise when comparing findings from different studies. For instance, 7 suggests that long-term, low-dose thioguanine administration poses minimal risk to the liver. However, other studies indicate that thioguanine can have negative effects on the liver. These discrepancies might stem from differences in the patients' background, thioguanine administration methods, or the types of drugs used in combination.

Practical Applications and Cautions

Thioguanine is used to treat conditions like psoriasis and leukemia. However, due to its potential for significant side effects, careful dosage adjustments are crucial. Dosage should be determined based on the patient's age, weight, disease severity, and any medications they are already taking. Regular blood tests and close monitoring for side effects are necessary while on thioguanine. It is essential to follow a doctor's instructions when taking thioguanine.

Limitations of Current Research

More research is needed to fully understand thioguanine's effects and safety. Specifically, further investigation of its genotoxic, hepatotoxic, and myelosuppressive risks is crucial. To optimize therapeutic benefit and minimize adverse effects, establishing optimal dosages and administration methods is vital.

Future Research Directions

Further research is crucial to gain a better understanding of thioguanine's effects and safety. Detailed investigation into its genotoxic, hepatotoxic, and myelosuppressive risks is a priority. Developing optimal dosages and administration methods to maximize therapeutic benefits and minimize adverse effects is essential. Furthermore, exploring the molecular mechanisms underlying thioguanine's action on cells can lead to the development of novel therapeutic strategies that enhance its efficacy and reduce side effects.

Conclusion

Thioguanine is a drug with diverse effects. It may be beneficial for treating conditions like psoriasis and leukemia, but its use necessitates careful consideration due to its potential for significant side effects. It is crucial to strictly follow a doctor's instructions when taking thioguanine. Further research is needed to enhance our understanding of its effects and safety, paving the way for safer and more effective treatment approaches.

Literature analysis of 28 papers
Positive Content
13
Neutral Content
7
Negative Content
8
Article Type
0
0
0
0
28
2.

Effects of azathioprine, 6-mercaptopurine, and 6-thioguanine on canine primary hepatocytes.

Author: LaDukeKathleen E, EhlingSarah, CullenJohn M, BäumerWolfgang

Hepatotoxicity

This study investigated the cytotoxic effects of azathioprine, 6-mercaptopurine, and 6-thioguanine on canine hepatocytes. The study found that these drugs adversely affected cell viability, but they did not have a significant effect on LDH or ALT activities or free glutathione depletion.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

4.

Effects of 6-thioguanine and S6-methylthioguanine on transcription in vitro and in human cells.

Author: YouChangjun, DaiXiaoxia, YuanBifeng, WangYinsheng

Cancer treatment
Cancer risk

Thiopurine drugs are chemotherapeutic agents but have been linked to therapy-related cancers. S(6)mG, a metabolic product of thiopurine drugs, has both inhibitory and mutagenic effects during transcription. It contributes, at least in part, to thiopurine-mediated cytotoxicity through inhibition of transcription and to potential therapy-related carcinogenesis via transcriptional mutagenesis.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.

Language : English

5.

Differential toxic effects of azathioprine, 6-mercaptopurine and 6-thioguanine on human hepatocytes.

Author: PetitElise, LangouetSophie, AkhdarHanane, Nicolas-NicolazChristophe, GuillouzoAndré, MorelFabrice

Hepatotoxicity

Thiopurines (azathioprine, 6-mercaptopurine, and 6-thioguanine) are widely used medications but have toxic effects. This study shows that human liver cells are less sensitive to thiopurines compared to rat hepatocytes, with toxicity occurring after 96 hours.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

6.

Differential effects of targeted disruption of thiopurine methyltransferase on mercaptopurine and thioguanine pharmacodynamics.

Author: HartfordChristine, VasquezErick, SchwabMatthias, EdickMathew J, RehgJerold E, GrosveldGerard, PuiChing-Hon, EvansWilliam E, RellingMary V

Leukemic drug therapy
Toxicity

This study investigated the effects of the thiopurine methyltransferase (TPMT) polymorphism on the pharmacokinetics and pharmacodynamics of mercaptopurine and thioguanine in a murine knockout model. The study found that the TPMT polymorphism significantly affects the metabolism of both drugs, with mercaptopurine being more sensitive than thioguanine. The results suggest that the TPMT polymorphism needs to be considered in optimizing drug therapy for individuals receiving thiopurine-based medications.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

7.

Toxicity of 6-thioguanine: no hepatotoxicity in a series of IBD patients treated with long-term, low dose 6-thioguanine. Some evidence for dose or metabolite level dependent effects?

Author: GilissenL P L, DerijksL J J, DriessenA, BosL P, HooymansP M, StockbrüggerR W, EngelsL G J B

IBD treatment
Short-term IBD results
Nodular regenerative hyperplasia

6-Thioguanine, used in inflammatory bowel disease, can cause nodular regenerative hyperplasia.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

9.

Selective radiosensitization of drug-resistant MutS homologue-2 (MSH2) mismatch repair-deficient cells by halogenated thymidine (dThd) analogues: Msh2 mediates dThd analogue DNA levels and the differential cytotoxicity and cell cycle effects of the dThd analogues and 6-thioguanine.

Author: BerryS E, DavisT W, SchuppJ E, HwangH S, de WindN, KinsellaT J

Radiosensitization
Selective targeting of MMR-deficient cells

Mismatch repair (MMR) deficiency can lead to drug resistance in cancer cells. This study found that halogenated thymidine analogs, such as IdUrd and BrdUrd, selectively target MMR-deficient cells for radiosensitization.

Comparative StudyResearch that compares multiple groups/interventions to determine differences/similarities in outcomes/characteristics.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, U.S. Gov't, P.H.S.Research funding provided by the Public Health Service (PHS).

Language : English

10.

Clinical clearing of psoriasis by 6-thioguanine correlates with cutaneous T-cell depletion via apoptosis: evidence for selective effects on activated T lymphocytes.

Author: MurphyF P, CovenT R, BurackL H, GilleaudeauP, CardinaleI, AuerbachR, KruegerJ G

Psoriasis treatment
T-cell depletion
Hematologic monitoring needed

6-Thioguanine was found to be an effective treatment for moderate to severe plaque-type psoriasis, possibly by inducing apoptosis in activated T lymphocytes.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.
Research Support, U.S. Gov't, P.H.S.Research funding provided by the Public Health Service (PHS).

Language : English

11.

Interactions of hydrated IIa and IIb group metal cations with thioguanine-cytosine DNA base pair: Ab initio and density functional theory investigation of polarization effects, differences among cations, and flexibility of the cation hydration shell.

Author: SponerJ, BurdaJ V, LeszczynksiJ, HobzaP

The structures and energies of the thioguanine-cytosine Watson-Crick (thioGC WC) base pair interacting with hydrated IIa (Mg2+, Ca2+, Ba2+) and IIb group (Zn2+, Cd2+, Hg2+) cations have been studied using ab initio techniques. The complexes of the thioGC WC base pair with hydrated cations have similar properties as the previously studied GC WC base pair. Soft Cd2+ and Hg2+ cations have a uniquely strong interaction with the thiogroup and induce substantial nonplanarity of the pairing.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.
Research Support, U.S. Gov't, Non-P.H.S.Research funding provided by US government agencies other than the Public Health Service.
Research Support, U.S. Gov't, P.H.S.Research funding provided by the Public Health Service (PHS).

Language : English

12.

Mercaptopurine in childhood leukaemia: the effects of dose escalation on thioguanine nucleotide metabolites.

Author: LennardL, WelchJ, LilleymanJ S

Higher peak TGN concentrations

Dose escalation of mercaptopurine in children tolerant of 100% dosage resulted in higher peak thioguanine nucleotide concentrations.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

13.

Polymerase chain reaction-directed DNA sequencing of bleomycin-induced "nondeletion"-type, 6-thioguanine-resistant mutants in Chinese hamster ovary cell derivative AS52: effects of an inhibitor and a mimic of superoxide dismutase.

Author: AnJ, HsieA W

Bleomycin mutagenesis

Bleomycin-induced mutagenesis in mammalian cells involves reactive oxygen species.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.
Research Support, U.S. Gov't, Non-P.H.S.Research funding provided by US government agencies other than the Public Health Service.
Research Support, U.S. Gov't, P.H.S.Research funding provided by the Public Health Service (PHS).

Language : English

14.

Polymerase chain reaction-based deletion screening of bleomycin induced 6-thioguanine-resistant mutants in Chinese hamster ovary cells: the effects of an inhibitor and a mimic of superoxide dismutase.

Author: AnJ, HsieA W

DNA damage

This study investigated the role of reactive oxygen species (ROS) in bleomycin mutagenesis in mammalian cells, providing evidence for the involvement of ROS in inducing deletion mutations.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

15.

Microcalorimetric evaluation of the effects of methotrexate and 6-thioguanine on sensitive T-lymphoma cells and on a methotrexate-resistant subline.

Author: BermudezJ, BäckmanP, SchönA

Continuous monitoring

Isothermal microcalorimetry was used to assess the effects of methotrexate (MTX) and 6-thioguanine (6-TG) on a human T-lymphoma cell line. MTX showed a dose-dependent inhibitory effect, while 6-TG had a faster inhibitory effect.

Comparative StudyResearch that compares multiple groups/interventions to determine differences/similarities in outcomes/characteristics.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

16.

Cytotoxic effects of vitamin A in combination with vincristine, daunorubicin and 6-thioguanine upon cells from lymphoblastic leukemic patients.

Author: PietersR, HuismansD R, LoonenA H, HählenK, VeermanA J

Treats acute lymphoblastic leukemia

Isotretinoin had additive antileukemic effects when combined with vincristine or daunorubicin, but did not potentiate the effects of these drugs or 6-thioguanine against acute lymphoblastic leukemia cells.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

17.

Genotoxic effects of radiotherapy and chemotherapy on the circulating lymphocytes of breast cancer patients. III: Measurement of mutant frequency to 6-thioguanine resistance.

Author: Sala-TrepatM, ColeJ, GreenM H, RigaudO, VilcoqJ R, MoustacchiE

Mutation due to radiation

Radiation therapy was found to be the primary factor contributing to increased mutant frequencies in peripheral blood lymphocytes of breast cancer patients. In a study of breast cancer patients who received either local radiotherapy followed by chemotherapy or chemotherapy followed by radiotherapy, the increase in mutant frequencies could be attributed solely to the effects of radiation.

Clinical TrialA clinical trial is a planned study conducted on humans to evaluate the efficacy and safety of pharmaceuticals, medical devices, and treatment methods. It aims to explore the possibilities of new treatments and improve the health of patients.
Comparative StudyResearch that compares multiple groups/interventions to determine differences/similarities in outcomes/characteristics.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

18.

Tolerance to O6-methylguanine and 6-thioguanine cytotoxic effects: a cross-resistant phenotype in N-methylnitrosourea-resistant Chinese hamster ovary cells.

Author: AquilinaG, GiammarioliA M, ZijnoA, Di MuccioA, DogliottiE, BignamiM

Chinese hamster ovary cells resistant to N-methyl-N-nitrosourea (MNU) and 6-thioguanine (6-TG) exhibited tolerance to both agents, including chromosomal damage, suggesting a common pathway of tolerance.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

19.

Effects of incorporation of 6-thioguanine into SV40 DNA.

Author: MaybaumJ, BainnsonA N, RoethelW M, AjmeraS, IwaniecL M, TerBushD R, KrollJ J

DNA synthesis inhibition

6-thioguanine (TG), an antileukemic agent, inhibits DNA synthesis by interfering with initiation of replication. The effect was correlated with TG incorporation into viral DNA.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.
Research Support, U.S. Gov't, P.H.S.Research funding provided by the Public Health Service (PHS).

Language : English

20.

Comparison of in vivo and in vitro effects of continuous exposure of L1210 cells to 6-thioguanine.

Author: MaybaumJ, MorgansC W, HinkL A

Antitumor effects
Increase survival time

This study investigated the effects of 6-thioguanine (TG) on cancer cells in both living animals and lab cultures. TG was most effective at killing cancer cells at low concentrations, leading to a delay in cell division. The appropriate clinical strategy is to use the lowest effective dose that produces the greatest delay in cell division.

Comparative StudyResearch that compares multiple groups/interventions to determine differences/similarities in outcomes/characteristics.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

24.

Occurrence of induced 6-thioguanine-resistant colonies in synchronized V79 cells after treatment with ftorafur. Effects of the S9 fraction.

Author: SlamenováD, DusinskáM, NádaskáM

Cytotoxic
Mutagenic

Ftorofur was a weak mutagen in V79 hamster cells when exposed in the presence of S9 microsomal fraction, but did not induce resistance to 6-thioguanine.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

25.

Cytotoxic and cytokinetic effects of 1-beta-D-arabinofuranosylcytosine, daunorubicin, and 6-thioguanine on HeLa cells in culture.

Author: FriedJ, PerezA G, DoblinJ M, ClarksonB D

This study investigated the interactions of 1-beta-D-arabinofuranosylcytosine, daunorubicin, and 6-thioguanine on the survival of HeLa cells. 1-beta-D-arabinofuranosylcytosine was found to protect cells against lethality induced by both 6-thioguanine and daunorubicin. The study suggests that 1-beta-D-arabinofuranosylcytosine can protect cells from the cytotoxic effects of other drugs, potentially by modulating DNA synthesis.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.
Research Support, U.S. Gov't, P.H.S.Research funding provided by the Public Health Service (PHS).

Language : English

26.

Investigation of the effects of the phorbol ester TPA on carcinogen-induced forward mutagenesis to 6-thioguanine-resistance in V79 Chinese hamster cells.

Author: KinsellaA R

TPA did not affect N'-methyl-N'-nitro-N-nitrosoguanidine (MNNG) induced forward mutagenesis in V79 Chinese hamster cells when using a replating assay.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

27.

The effects of inhibitors of DNA biosynthesis on the cytotoxicity of 6-thioguanine.

Author: LeeS H, SartorelliA C

Cytotoxicity

The antiproliferative activity of 6-thioguanine (6-TG) was examined using cultured L1210 leukemia cells. The presence of metabolic inhibitors of DNA synthesis did not increase the cytotoxicity of 6-TG, but instead protected cells against it, suggesting that DNA replication was essential for the expression of 6-TG cytotoxicity. 6-TG was found to cause structural changes in DNA, suggesting that these lesions may be involved in its cytotoxic action.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.
Research Support, U.S. Gov't, P.H.S.Research funding provided by the Public Health Service (PHS).

Language : English

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