We aim the development of anticancer drugs with less impact on normal cells, and one of our specific approaches is to target cell cycle G2 checkpoint.
Cell cycle
Cell cycle is the process that a cell is divided in 2 cells.
In this process, there are S phase to replicate DNA, M phase to devide into 2 cells, and G1 and G2 phases as pre-process of each phase.
When a cell continues cell division with DNA damage, most of them (regardless of normal or cancer cells) undergo apoptosis. In order to prevent this, cells have "checkpoint" mechanism to stop the progress of cell cycle temporarily to repair DNA damage. Checkpoints in "G1 phase" and "G2 phase" have been well known as major checkpoints (hereinafter referred as "G1 checkpoint" and "G2 checkpoint").
Adverse drug reactions of conventional anticancer drugs and cell cycles
Most of conventional anticancer drugs abrogate cell division without differentiating normal cells or cancer cells, and as a result, they show their efficacy on actively dividing and proliferating cancer cells. On the other hand, many tissues, including alimentary canal mucosa, hematopoietic cells of bone marrow, and hair root cells are maintained by active division and proliferation, as like cancer cells. Maintenance of these tissues becomes difficult when conventional anticancer drugs impartially targeted cells to abrogate, including those normal cells. Generally well known adverse drug reactions of anticancer drugs, such as diarrhea, vomiting, myelosuppression, and hair loss are caused by such mechanism.
G2 checkpoint abrogation
When anticancer drug targets G2 checkpoint, it is considered that the anticancer drug possibly attacks cancer cells only, without having impact on normal cells, thus fewer side effects. In normal cells, both G1 and G2 checkpoints have functioned, and, above all, G1 checkpoint functions powerfully to check DNA damage at cell division. When DNA has any damage, cell cycle is temporarily stopped in G1 phase in normal cells to try to repair the damage. On the other hand, cancer cells disturbs or dysfunctions G1 checkpoint from the beginning in order to be cancer cells. As a result, most of cancer cells lost G1 checkpoint and depend on G2 checkpoint to repair DNA damage at cell division. On this account, when DNA has any damage, cell cycle is temporarily stopped in G2 phase in cancer cells to try to repair the damage.
In that time, if the mechanism of G2 checkpoint is lost, it means cancer cells to lose the only checkpoint. Therefore, DNA damage due to anticancer drug is not repaired in cancer cells and cell death is induced. On the other hand, it is considered that there is less impact on cell division of normal cells because G1 checkpoint functions normally although the function of G2 checkpoint is abrogated.
From such reasons, the drug discovery concept to target G2 checkpoint is considered the effective approach to develop anticancer drug with fewer side effects.
Expected new mechanism of drug efficacy
Article from Journal of National Cancer Institute (JNCI), US (July 20, 2005)
The concept of G2 checkpoint abrogation attracted attention since before; special feature article was issued in JNCI when we started a clinical study.
We aim the development of anticancer drugs with less impact on normal cells, and one of our specific approaches is to target cell cycle G2 checkpoint.
