I. Crosslinking agents
Mechanism (alkylating agents)
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Must be (or become) strong electrophiles (as charged molecules generally do not cross the blood/brain barrier very well)
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Attack on cell nucleophiles: -SH of protein, -N- of protein or DNA base (esp. N7 position of guanine), =O of DNA base or phosphate
- DNA damage includes:
- crosslinking (esp. if bifunctional agent)
- miscoding of DNA bases (esp. G-T pairing)
- DNA strand breakage (depurination)
Although crosslinking agents are dependent upon proliferation, these agents ARE NOT CELL CYCLE SPECIFIC (i.e., they are CCNS) because the alkylation reactions that initiate cell death can occur during any phase of the cell cycle. However, primary toxicity occurs in late G1 and S phase, with cell cycle arrest occuring in G2. |
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- method of selective toxicity:
- DNA damage normally activates a cell cycle checkpoint that is dependent on the p53 gene
- 50% of human cancers have a mutated or absent p53 gene à cancer cells cannot repair the DNA alkylation or undergo apoptosis, making these drugs more effective in those types of cancers
- normal cells stop the cell cycle and repair the damage