G2 checkpoint abrogation as a cancer specific, cell cycle disruption

Abstract

The majority of cancer cells are thought to have accumulated the necessary mutations for oncogenesis as a result of disrupting the cell cycle G1 checkpoint, leading to the replication of damaged DNA. In fact, all of the historical suspects of oncogenesis - mutagens, viruses and heredity - have been shown to impair G1 checkpoint function. As a result, more than half of all human cancer cells with impaired G1 checkpoint function rely on the G2 checkpoint to survive against the DNA damage which most cytotoxic cancer treatments cause. The G2 cell cycle checkpoint is not used heavily by normal cells, which makes a cell cycle G2 checkpoint abrogation strategy attractive for the battle against cancer. Early studies focused on non-specific G2 checkpoint abrogators, including; caffeine, pentoxifylline, fostriecin, okadaic acid and UCN-01. The search for more selective G2 checkpoint abrogators has been ongoing since the central molecular mechanism of the G2 checkpoint was revealed in 1997. So far most of the candidate compounds target the CHK1 and/or CHK2 proteins. Among the more selective G2 abrogators, the first to go into human clinical trials since UCN-01 will be the synthetic peptide CBP501.