DNA repair in Cancer Therapy: A Study
- Vishwanth M
- Jan 29, 2023
- 2 min read
An alkylating antineoplastic agent is one that attaches an alkyl group (CnH2n+1) to DNA and is used to treat cancer. The purine ring's nitrogen atom at position 7 of the guanine base of DNA is where the alkyl group is joined. Cancer cells are more vulnerable to DNA damage, such as being alkylated, than healthy cells because they multiply more quickly and with less error-correcting than healthy cells. Several malignancies are treated with alkylating drugs. However, they are also toxic (cytotoxic) to healthy cells, especially those that divide rapidly, like those in the gastrointestinal system, bone marrow, testicles, and ovaries, which might reduce fertility. Despite the DNA of both healthy and cancerous cells being destroyed in an unspecific manner, their aim is the DNA, and they exert tumor-specific effects.
At least 12 distinct DNA lesions are brought on by substances with methylating characteristics, such as temozolomide, procarbazine, dacarbazine, and streptozotocine. These are restored through base excision repair and damage reversal pathways involving the alkyl transferase MGMT and the alkB homologous protein ALKBH2 (BER). In high-grade malignant gliomas, there is a direct link between the degree of MGMT expression and the therapeutic response, supporting the idea that O6-methylguanine and, for nitrosoureas, O6-chloroethylguanine are the most important toxic damages at therapeutically important dosages.
Clinical trials are being conducted to determine the impact of MGMT inhibition on the success of therapy since MGMT has a major impact on the result of anti-cancer therapy and is a predictive marker of the efficacy of methylating anticancer medicines. Mismatch repair, homologous recombination (HR)-mediated DNA double-strand break (DSB) repair, and DSB signalling are other DNA repair processes involved in methylating drug resistance. Base excision repair and ALKBH2 may also be involved in alkylating drug resistance, and their downregulation may affect drug sensitivity, particularly in cells that express high levels of MGMT and at high doses of temozolomide, but it is still unknown how important these factors are in a therapeutic setting.
Due to CpG promoter methylation, MGMT is typically downregulated in cancer cells (up to 40% in glioblastomas). Isocitrate dehydrogenase mutations typically occur in grade III astrcytomas (IDH1). These cancers respond to therapy remarkably well. The IDH1 mutation affects ALKBH2 activity, which in turn affects DNA repair. P53, which frequently maintains transactivation activity (wildtype) in malignant gliomas, acts as a master switch between life and death.
Representation of the different DNA response pathways:
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