Treatment
The standard first-line treatment for malignant gliomas includes the use of alkylating agents such as temozolomide, which is widely used, sometimes in combination with ionizing radiation (7). This alkylating agents exist in the environment, like in fuel combustion or cigarette smoke, in diet, such as in processed meat or could exist as a product of endogenous metabolic processes (8, 9). This alkylating agents, when in low concentrations, could be mutagenic and carcinogenic but another cause of human exposure to this type of agents is cancer chemotherapy, in which they are choose due to their ability to induce extensive DNA damage and cell death (9). They also can induce a great quantity of DNA lesions because they can react with different …show more content…
It is administered orally and like other cytotoxic alkylating agents, it easily penetrates the blood-brain barrier (12). Temozolomide when orally administered is converted to 5-(3-methyltriazen-1-yl)imidazole-4-carboximide (MTIC) in water/blood with little or no enzymatic component (1). MTIC is broken down to methyldiazonium cation and 5-aminoimidazole-4-carboxamide (AIC). AIC is excreted through the kidneys and methyldiazonium cations deliver methyl groups to DNA (1). O6-methylguanines are formed when these methyl groups are transferred to the 6th position of oxygen atoms of guanine. During DNA replication, O6-Methylguanine mispairs with thymine instead of cytosine. The post-replication mismatch repair system (MMR), can recognize the O6-methylguanine:thymine mispair, which removes a daughter strand along with the thymine, introducing strand breaks and leaving the O6-methylguanine to again pair with thymine during gap filling. Double-strand breaks can form if replication of the gapped structure occurs. If not repaired by the recombination repair pathways, they result in cell death …show more content…
The repair by the BER is helped by a particular DNA glycosylase which by hydrolyzing the N-glycosidic bond, recognizes and removes modified bases. The MPG (also known as 3-alkyladenine-DNA glycosylase (AAG)) is the glycosylase, in human cells, responsible for the removal of N-methylated bases. MPG is a type I glycosylase and by removing the modified bases leaves an apurinic/apyrimidinic site (AP site) in the DNA which then the MPG releases the N3MeA, N7MeG and N3MeG from DNA making the cells more susceptible to alkylating agents
The standard first-line treatment for malignant gliomas includes the use of alkylating agents such as temozolomide, which is widely used, sometimes in combination with ionizing radiation (7). This alkylating agents exist in the environment, like in fuel combustion or cigarette smoke, in diet, such as in processed meat or could exist as a product of endogenous metabolic processes (8, 9). This alkylating agents, when in low concentrations, could be mutagenic and carcinogenic but another cause of human exposure to this type of agents is cancer chemotherapy, in which they are choose due to their ability to induce extensive DNA damage and cell death (9). They also can induce a great quantity of DNA lesions because they can react with different …show more content…
It is administered orally and like other cytotoxic alkylating agents, it easily penetrates the blood-brain barrier (12). Temozolomide when orally administered is converted to 5-(3-methyltriazen-1-yl)imidazole-4-carboximide (MTIC) in water/blood with little or no enzymatic component (1). MTIC is broken down to methyldiazonium cation and 5-aminoimidazole-4-carboxamide (AIC). AIC is excreted through the kidneys and methyldiazonium cations deliver methyl groups to DNA (1). O6-methylguanines are formed when these methyl groups are transferred to the 6th position of oxygen atoms of guanine. During DNA replication, O6-Methylguanine mispairs with thymine instead of cytosine. The post-replication mismatch repair system (MMR), can recognize the O6-methylguanine:thymine mispair, which removes a daughter strand along with the thymine, introducing strand breaks and leaving the O6-methylguanine to again pair with thymine during gap filling. Double-strand breaks can form if replication of the gapped structure occurs. If not repaired by the recombination repair pathways, they result in cell death …show more content…
The repair by the BER is helped by a particular DNA glycosylase which by hydrolyzing the N-glycosidic bond, recognizes and removes modified bases. The MPG (also known as 3-alkyladenine-DNA glycosylase (AAG)) is the glycosylase, in human cells, responsible for the removal of N-methylated bases. MPG is a type I glycosylase and by removing the modified bases leaves an apurinic/apyrimidinic site (AP site) in the DNA which then the MPG releases the N3MeA, N7MeG and N3MeG from DNA making the cells more susceptible to alkylating agents