Interference with DNA repair mechanisms of mammalian cells: cell cycle dependence.

Agents that prevent repair of lesions in DNA increase cell death. Caffeine enhances lethality of agents such as HN2. We propose that damaged cells stop in G2 phase until repair is completed, and caffeine prevents this G2 arrest. Therefore caffeine lets damaged cells go through mitosis; their chromosomes are shattered and they die. This action of caffeine requires rapid synthesis of protein(s). Some classes of damage by alkylating agent (methyl methane sulfonate (MMS] are removed slowly in human cells, followed by rapid repair synthesis. Lethality results if gaps created during repair of DNA are present during semiconservative replication. Nicotinamide analogs prevent ligation, the gaps persist, and lethality is greater. This effect is S phase specific. Further experiments may specify conditions and agents giving better therapeutic results than can be obtained with anticancer drugs used alone.