DNA-interactive anticancer agents - Methylating agents Flashcards Preview

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Flashcards in DNA-interactive anticancer agents - Methylating agents Deck (10)
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1
Q

How do methylating agents work?

A

work by methylating guanine bases (CH3-DNA) within the major groove of DNA, predominantly at the guanine N7 and O6 positions

2
Q

Name examples of Methylating agents

A

Dacarbazine, Procarbazine, Temozolomide

3
Q

How does Dacarbazine work and what is it used for

A

Methylates DNA at guanine N7 position. It is used as a single agent to treat metastatic melanoma, or in combination in Hodgekin’s disease

4
Q

How does Procarbazine work?

A

N-oxidation followed by subsequent rearrangement to produce methyl radicals which act as methylating agents towards guanine residues

5
Q

Procarbazine, side effects, uses and administration

A

Orally administered, hence can cause side effects of nausea. other side effects are Myelosuppression and hypersensitivity. Used in Hodgekin’s disease.

6
Q

Temozolomide - can work in two ways. What are they?

A

chemical and biochemical

7
Q

Chemical mechanism of Temozolomide

A
  • Hydrolytic cleavage of the tetrazinone ring at physiological pH to give unstable MTIC, which undergoes further cleavage to give stable molecule (5-aminoimidazole-4-carboxamide) and highly reactive (methyldiazonium).
  • The highly reactive species methylates DNA and in the process forms other stable molecules such as N2 and CO2. The formation of the stable molecules is the driving force of the drugs MOA.
8
Q

Biochemical mechanism of Temozolomide

A
  • Drugs activity depends on the ability of the mismatch repair enzymes (MMRs) to detect the wobble base-pair formed during replication of drug-modified DNA.
  • The methylated guanine looks like an A to the MMR enzyme, so it matches it with a T.
  • This leads to the MMR-induced strand to break, triggering arrest of cell cycle.
9
Q

Temozolomide - side effects, benefits, and route of administration

A

Malignant glioma, melanoma.High selectivity at cellular level, Very good oral bioavailability uptake and distribution properties – Particularly: It can penetrate the CNS leading to tumor localization

10
Q

why does Temozolomide have such high selectivity

A

Due to slightly different pH environments in normal compared to tumor cells coupled with a reduced capacity to repair the DNA.