Tioguanine formerly thioguanine (BAN

British Approved Name

A British Approved Name is the official non-proprietary or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia...

), is a drug

Medication

A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

 that is used in the treatment of cancer

Cancer

Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

.

It belongs to the family of drugs called antimetabolite

Antimetabolite

An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolates that interfere with the use of folic acid...

s. It is a guanine

Guanine

Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...

 analog.

Uses

Its principal use is in acute leukaemias and chronic myeloid leukaemia.

It has been investigated for use in treatment of psoriasis

Psoriasis

Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...

.

Pharmacology

As a guanine analogue, it is transformed inside the cell into 6-thioguanilyic acid (TGMP), which, by pseudofeedback interference with purine biosynthesis, interferes with the synthesis of guanine nucleotides. Some of its activity may also be due to the incorporation of thioguanine nucleotides into both RNA

RNA

Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....

 and DNA

DNA

Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

, but the end-result is inducing cell cycle

Cell cycle

The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...

 arrest and apoptosis

Apoptosis

Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

. It is metabolized via methylation by thiopurine methyltransferase

Thiopurine methyltransferase

Thiopurine methyltransferase or thiopurine S-methyltransferase is an enzyme that methylates thiopurine compounds. The methyl donor is S-adenosyl-L-methionine, which is converted to S-adenosyl-L-homocysteine....

.

Mechanism of cell cycle arrest and cell death

After incorporation into DNA, the thiocarbonyl of thioguanine has a tendency to be methylated. This produces a base similar to 6-O-methylguanine

6-O-Methylguanine

6-O-Methylguanine is a derivative of the nucleobase guanine in which a methyl group is attached to the oxygen atom. It base-pairs to thymine rather than cytidine, causing a G:C to A:T transition in DNA....

.

During a second round of replication, the mismatch repair system will recognize the mismatch between the methylated base and cytosine

Cytosine

Cytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...

. The attempt to repair such a mismatch is abortive since no nucleotides can be properly matched with the methylated base. This leads to persistent 100-200 base single strand breaks. Such a genotoxic stress will trigger cell cycle arrest and cell death. In this regard, thioguanine and mercaptopurine

Mercaptopurine

Mercaptopurine is an immunosuppressive drug.It is a thiopurine.-Uses:...

, although categorized as antimetabolites, exert their functions more like a genotoxic methylating agents, such as temozolomide

Temozolomide

Temozolomide Temozolomide Temozolomide (brand names Temodar and Temodal is an oral alkylating agent which can be used for the treatment of Grade IV astrocytoma — an aggressive brain tumor, also known as glioblastoma multiforme as well as melanoma, a form of skin cancer...

, which methylates DNA and generate 6-O-methylguanine and cytosine mismatch.

The ability of thioguanine and mercaptopurine to trigger genotoxic stress is also exemplified by their treatment-related acute myeloid leukemia

Acute myeloid leukemia

Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...

 (AML), which is uncommon for antimetabolites, but common for alkylating agents and topoisomerase inhibitor

Topoisomerase inhibitor

Topoisomerase inhibitors are agents designed to interfere with the action of topoisomerase enzymes , which are enzymes that control the changes in DNA structure by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle.In recent years,...

s.