DNA-interactive anticancer agents - Methylating agents

Question 1

How do methylating agents work?

Answer 1

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

Question 2

Name examples of Methylating agents

Answer 2

Dacarbazine, Procarbazine, Temozolomide

Question 3

How does Dacarbazine work and what is it used for

Answer 3

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

Question 4

How does Procarbazine work?

Answer 4

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

Question 5

Procarbazine, side effects, uses and administration

Answer 5

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

Question 6

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

Answer 6

chemical and biochemical

Question 7

Chemical mechanism of Temozolomide

Answer 7

• 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.

Question 8

Biochemical mechanism of Temozolomide

Answer 8

• 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.

Question 9

Temozolomide - side effects, benefits, and route of administration

Answer 9

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

Question 10

why does Temozolomide have such high selectivity

Answer 10

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